A SHORT STROLL THROUGH THE HISTORY OF CANCER
A FEW MONTHS BEFORE STARTING TO WRITE THIS BOOK I WAS PUFFING up a steep climb in the Drakensberg Mountains in search of one of the sites of rock paintings that are found throughout the region of what is now Kwa-Zulu-Natal. These artworks are the legacy of the San people who first moved to that part of the world about 8,000 years ago, and some of the paintings are over 2,000 years old. When we finally reached our goal, my first thought, apart from "thank heavens we can stop climbing," was what amazingly clear pictures these are of the animals with whom the San shared southern Africa. The most striking message, of course, was of the critical importance of hunting in the lives of those people. After a few minutes, however, I found myself musing on less obvious points. First that it was a bit surprising—given that securing your next meal was such a struggle, to say nothing of ensuring that you didn't become something else's dinner—that at least some folk had time to absorb the world around them and, moreover, come up with ways of recording what they saw. But then it occurred to me that, what with all the spearing and butchering that life entailed, these ancients must have built up quite a decent knowledge of anatomy, at least of wildebeest, gnu, and suchlike. Perhaps some far distant forerunner of Charles Darwin had sat on the very rock I was occupying and ruminated on how similar the layout of the bits was when you carved open the bodies of animals that looked completely different on the outside.
We shall never know, of course, because terrific artists though they may have been, the San had no written language by which they could pass on their knowledge. The first known written language is Sumerian, and records in cuneiform script have been dated as far back as 3000 BC. Cuneiform evolved through the practice of impressing shapes into clay, and pottery fragments bearing impressed markings have very recently been dug up in Pakistan that are estimated to be as old as 5,500 years. However, for the most ancient texts that tell a medical story, we have to turn to the papyrus records of the Egyptians. This method of recording may be almost as old as clay tablets, but its importance in the story of cancer emerged from the travels of an American called Edwin Smith, who visited Luxor in 1862. There he bought the manuscript that bears his name and that eventually came into the possession of the New York Academy of Medicine. Estimated to date from approximately 1600 BC, it was first translated in 1930 by James Breasted of the University of Chicago. The Edwin Smith papyrus is notable in at least two ways. First, particularly in its transcribed form as a pictograph, in appearance it is infinitely more beautiful than any twenty-first-century scientific paper. Second, it is in effect a set of very concise clinical reports, each presented under the headings Examination, Diagnosis, and Treatment, dealing with forty-eight cases. Almost all refer to patients who have suffered serious injuries ("a wound in his head penetrating to the bone of his skull"), indicative of evolution from the days of the San people at least in the capacity of humans to slaughter each other. However, two of the records refer to what Breasted translated as "tumors": "Instructions concerning tumors with prominent head in his breast: thou findest that the swellings have spread with pus over his breast, (and) have produced redness, while it is very hot therein, when thy hand touches him. An ailment which I will treat with the fire-drill" and "Instructions concerning bulging tumors on his breast (meaning swellings): findest them very cool, there being no fever at all therein. There is no treatment."
It seems probable that the first of these may have been an abscess—a build- up of dead cells at a site of infection—rather than a tumor, and that the symbol for a swelling was used for both. That would be consistent with the abscess being treatable with a fire-drill, assumed to mean cauterization using a red-hot iron, a substance with which the Egyptians were certainly acquainted, and a technique subsequently much practiced in Western movies. More notable from our point of view is the fact that the writer was sufficiently astute and honest to record that for "bulging tumors" there was nothing he could do, a state of affairs that arises to this day with some cancers despite the phenomenal progress that we will chart in our story.
The Egyptians also developed a considerable range of medicines; in the Edwin Smith papyrus, preparations of ostrich eggs and of honey are frequently recommended for the treatment of wounds. More perturbingly, their medicines often included minerals such as arsenic that we might expect to encounter in an Agatha Christie novel but not on the shelves of our local pharmacy. We now know that, quite apart from being a poison, arsenic can actually help cancers to develop. Nevertheless, both the Egyptians and the ancient Greek and Chinese physicians who used it to treat many conditions might have been on to something, because we will meet arsenic again when we consider recent developments in drug therapy for cancers.
THE GREEKS HAD A WORD FOR IT
Perhaps the most famous name in medical history is that of the Greek physician Hippocrates, often referred to as the "Father of Medicine," who lived around 400 BC. In fact, much of the story of his life that has come down to us is probably mythical, but he is credited with being the first physician to take a scientific view of disease as a natural process occurring within the body, as opposed to being visited upon us by some sort of magical, quasi-religious force. Certainly the writings attributed to him are a model of clarity in summarizing the most detailed observations following, albeit unknowingly, the pattern of the Edwin Smith papyrus. The field of cancer is indebted to Hippocrates for its name. He noted that tumors often had a high density of blood vessels, thought to resemble the limbs of a crab, the Greek for which gave us the word "carcinoma," the most common type of cancer in humans. We might also note in passing that Hippocrates was the first to use the Greek word "apoptosis," meaning the "dropping off" of petals or leaves from plants or trees, in a medical context. Hippocrates was actually describing gangrene, in which tissues become black and decay as a result of infection or restricted blood supply; we shall return to the subject of dying cells a little later in the story.
Galen, a countryman of Hippocrates, followed his footsteps some six hundred years later to become a prolific writer and radical surgeon—he was the first to treat cataracts and to employ taking the pulse as a means of diagnosis, and is generally credited with being the first to use the word "cancer," the Latin for "crab."
Avicenna (also known as Ibn Seena), the Persian physician, is thought of as a philosopher by virtue of his mastery of seemingly all science known at that time (around AD 1000), together with Islamic theology. He is credited with a large amount of written work, but his contribution to cancer was through a fourteen-volume Canon of Medicine. This became essentially the encyclopedia of medicine for the next seven hundred years not only in the Islamic world but also in Europe as a result of its being translated into Latin. It includes the first description of surgery for cancer and also a treatment using an extract from the plant hindiba.
LAYING THE FOUNDATIONS
A substantial period separated the observations of Hippocrates and his school from the first specific findings relating to cancer, which did not come until the eighteenth century and the dawn of the age of modern medicine. To a considerable extent, this long period reflects the fact that so often in science progress is limited by the tools available at the time; it was not until the seventeenth century that a significant surge of innovative intellectual activity signaled the onset of real progress. Perhaps the clearest indicator of the dawn of a new age was the founding of the Royal Society of London in 1660 under a charter granted by King Charles II. It evolved as a forum for a group of luminaries who had been exchanging information and ideas about science in an informal way and had become known as the Invisible College. The Royal Society is still going strong 350 years later in its elegant home just off The Mall in London. It is the British precursor of Academies of Science that many other countries have since set up and it is the oldest such learned society in the world.
Great strides in the history of humankind often reflect unique confluences of gifted individuals, and rarely can more brilliant galaxies have assembled than at the first gatherings of the Society. The founders included Christopher Wren, one of the greatest of all architects, and Robert Boyle, the founder of modern chemistry, immortalized by the fundamental law that bears his name (the one that says a gas fills less space the more you squeeze it—or, before any physicists have a fit, pressure multiplied by volume is constant). The Royal Society was shortly to publish Isaac Newton's Principia Mathematica, and Newton himself became president in 1703. One of the other founders was the outstanding Robert Hooke, a polymath if ever there was one. Hooke was born, the youngest of four children, into an ecclesiastical family living on the Isle of Wight. Fortunately, he was fascinated from his earliest years by all things mechanical, building a working wooden clock when still a youngster, and was thus saved from following the family tradition. This was a seriously good thing because, even among the bright sparks of the Royal Society, Hooke turned out to be rather special. He collaborated with the chemist Robert Boyle, who devised his celebrated law using vacuum pumps made by Hooke. He was a skilled surveyor and architect, coming up with a street plan for rebuilding London after the Great Fire (they didn't use it, which is why to this day London's chaotic layout reflects the Middle Ages rather than Hooke's grid-like vision). He was an astronomer, the first person to explain that light behaves like a wave and that as things get hotter, they expand. Moving into biology, he had a go at skin grafts and carried out the first recorded blood transfusion—on a dog. This prompted similar experiments on humans, mainly in France. However, as the subjects tended to die, in contrast to Hooke's dog, transfusions were abandoned until biochemistry was able to reveal the problem of matching blood groups.
For none of this, however, did Hooke become famous, and it required two further efforts to ensure his immortality. The first was working out his eponymous law of elasticity (how far a spring stretches depends on how hard you pull it). While Hooke's Law will forever be a fundamental of physics, his massive impact on biology followed from starting to play with microscopes. Simple lenses for magnifying objects had begun to be used by the late 1500s, and by 1624 Galileo Galilei had devised a compound microscope (one with two lenses), which is essentially the design used to this day. However, while Galileo's inclination was to point his magnifier at the stars, Hooke looked in the other direction, so to speak, and produced the first images of things in the natural world that are too small to be seen by the unaided eye. As it would be a further two hundred years before someone came up with the idea of photography, Hooke had to draw what he saw—and what a stunning artist he showed himself to be! His incredibly detailed pictures include a flea, a louse, and a gnat and he put them together in 1665 as the first scientific best seller, Micrographia, published by the Royal Society. Though not apparent at the time, its impact on the subject of cancer was immense. This came about in a slightly curious way because, in addition to various insects, Hooke pointed his microscope at plants, specifically at a piece of cork, for which the main source is the cork oak. Hooke's drawing shows vividly the regular structure revealed through his microscope that to him resembled the shape of a monk's cell. Thus for the first time was the basic unit of life revealed, and Hooke simply used the word "cell" to describe it (Plate 1).
While it was indeed many years before it became clear that cancer was a reflection of something going wrong with cells in animals, Hooke's observations and the other great scientific events of that time opened the eyes of all with an interest in the natural world to the notion that, by observation and intelligent deduction, it might be possible to make sense of what hitherto had been explained only by religious mysticism.
This realization prompted a gradual trend to thoughtful analysis of cause and effect, one of the first exemplars being an Italian, Bernardino Ramazzini. He noted in 1713 that nuns rarely fell victim to cervical cancer and yet were particularly prone to breast cancer and concluded that this might have something to do with their lifestyle. Of course, his observations reflect the fact that cervical cancer most commonly results from the transmission of a virus during sexual contact and that the hormonal changes associated with pregnancy are a strong protective factor against breast cancer. As nuns are generally held to avoid both these activities, they could perhaps be viewed as losing on the swings what they've gained on the roundabouts.
Shortly thereafter, in 1761, Dr. John Hill of London sparked a long-running debate by concluding that snuff inhalation, popular in those days among the male gentry, might cause nasal cancer. The snuff saga persisted for over two hundred years until, in 1985, the Cancer Research Campaign brought its authority to bear by stating "there is no evidence of any association with cancer or other health risk in the snuff produced in this country. For this reason, snuff seems an entirely acceptable substitute for cigarette smoking and could be recommended for addicted cigarette smokers since, if they could substitute snuff taking for cigarette smoking, they would greatly reduce the risk to their health." Well, that piece of advice could scarcely be said to have made a major impact, but it did make the point that, in a sense, the good doctor Hill was on the right lines in thinking that something you inhaled might give you cancer. However, the critical difference between snuff inhalation and smoking is combustion—it's burning tobacco that releases chemicals that cause cancer, over forty of which have now been identified in cigarette smoke.
A more notable physician of the time was Percivall Pott, mainly because he tended to be right. Pott worked at Saint Bartholomew's Hospital in London, and to this day his name flits before the consciousness of medical students because it is given to a particular type of ankle fracture and also to a form of tuberculosis of the backbone. Seemingly, Pott broke his leg when he was thrown from his horse while making a house call. He broke both the bones in his lower leg and they penetrated the skin. In those days the recommended treatment was amputation, a strategy on which Pott wasn't too keen, and instead he tried binding up the limb and resting it. He made a full recovery, spending his convalescence writing a treatise on the management of fractures and dislocations. This story indicates that Pott, as well as being a gifted surgeon, was an able scientific observer, as he showed by spotting that chimney sweeps often succumbed to cancer of the scrotum. In 1775, rather than using mechanical aids, chimneys were swept by boys shinning up the vents, a job that they often carried out naked. Those who were astute or coy enough to wear a leather garment about their nether regions were protected and Pott, comparing the incidence of cancer with the modesty of the sweeps, concluded that the cancer was caused by soot accumulating in the folds of the scrotum. This was the first identification of an occupational exposure to cancer-causing agents, and it led to other such risks being recognized. However, soot, like tobacco smoke, is a complex mixture, and it took until 1930 for Ernest Kennaway to isolate the first specific chemical that can promote cancer (i.e., it's a "carcinogen"). The stuff Kennaway pulled out was a "fused hydrocarbon," which is the main carcinogen in both soot and tobacco, though we can also get doses of them from forest fires and asphalt. We now know that quite a number of these "promoters" are converted into harmful forms only once they get inside our bodies: the more deeply you inhale, the more this happens—and the more likely you are to get lung cancer.