The Miraculous Fever-Tree Read online

  Or perhaps the Plasmodium skipped that phase altogether. The larvae that emerged from the eggs began to eat, Manson suggested, ‘and one of the first things they eat if they get the chance, is the dead body of their parent, by now soft and sodden from decomposition and long immersion’. Through this insect cannibalism, Manson believed, the parasite would enter the larvae, and thence the adult insect.

  As a biological construction, Manson’s theory was as ingenious as it was imaginative. The trouble was that it would, in almost every respect, turn out to be quite wrong. The analogy between filariae and Plasmodium would not stand up to scrutiny. Man did not acquire malaria nor the filarial worm by drinking a watery cocktail of dead mosquitoes. In the absence of conclusive evidence to the contrary, Manson clung to his theory. There was something quite Victorian about an entomological melodrama tinged with cannibalism and filial greed, but deep down, Manson wanted more than just operatic satisfaction; he wanted to be proved right. And Ross, he decided, was the man to do it.

  Aboard the SS Ballarat on his return voyage to India, Ross honed the skills he had learned from Manson by analysing blood he drew from his fellow passengers and dissecting the cockroaches he asked the P&O seamen to catch for him.

  Having two days in Bombay before he proceeded to join his regiment at Secunderabad, Ross went straight to the Civil Hospital to see if he could find any cases of tertian fever. In his notebook he described the case of a woman from Ahmedabad whose spleen showed the classic swelling of a malaria patient. Fortunately, for Ross at least, she had not yet been given quinine, which would have affected her blood sample. Alongside this entry he jotted down the task that lay ahead, as he and Manson had conceived it: to study Plasmodium, not in man, but in the mosquito, ‘a thing which had never been yet attempted’. To achieve that, he would have to demonstrate that Plasmodium could survive in the mosquito, then find out what happened to them inside their insect host, how they lived and how they developed. None of this would be straightforward, but Ross was eager to get going.

  On 1 May, from Secunderabad, he began his first letter to his old mentor: ‘Dear Dr Manson, I write to report progress, and hope you will excuse size of paper.’ For the next four months, Ross dedicated himself to his researches. He began by catching mosquitoes, but found that they ailed and died, or would not bite. Perhaps, he speculated, it was the ‘awful’ heat and dry wind ‘like the blast of an engine furnace’. He began raising mosquitoes from larvae, feeding them on patients with parasites in their blood, then killing and dissecting them, looking for signs of parasites in their stomachs. He set up controlled experiments at different temperatures and timescales. Slowly he began to gather evidence that the parasitic crescents Laveran had seen in human blood actually turned into spheres within the mosquito’s stomach, which meant they were beginning to fill out and grow. But why?

  Manson, anxious that Ross’s work should become better known, and worried lest he become discouraged, suggested that he write up his findings for publication. The heat in central India was growing more unforgiving as the summer wore on, and Ross couldn’t use a fan in his small laboratory for fear that it would blow his mosquitoes away. Manson wrote entreating him not to give up: ‘The malaria germ does not go into the mosquito for nothing, for fun or for the confusion of the pathologist. It has no notion of a practical joke. It is there for a purpose and that purpose depend upon it is its own interests – germs are selfish brutes.’

  In September 1895 Ross was ordered away from Secunderabad. The city of Bangalore in southern India had been swept by an epidemic of cholera, and Ross, with his diploma in public health, was deputed to clean up the native quarter where the epidemic had begun. Organised and energetic, if occasionally overbearing, Ross found he had a gift for dealing with crises. The epidemic died down over the winter, but the following summer it flared up again. Ross once again sprang into action. He began by closing the public wells. ‘We did what we could,’ he would write in his Memoirs twenty-eight years later. ‘We closed the wells in batches; we disinfected them over and over again; we told the people to boil their drinking water and provided it ourselves; we gave them hot coffee and medicine early in the morning; we disinfected backyards, drains, and rooms occupied by the dying. All in vain. The Angel of Death had descended amongst them and smote the poor wretches right and left.’

  Ross worked from early in the morning until midnight. Inevitably, his work on mosquitoes and the malaria Plasmodium slowed. In April 1896, Manson wrote to him, ‘I … regret very much that these [duties] have taken you away from what I look upon as your proper work – the investigation of the mosquito stage of malaria.’ By October he was even more concerned – less about Ross losing interest than that the two of them might be beaten by a foreigner in their quest for a provable theory of how mosquitoes transmit malaria. ‘Laveran is working up the Frenchmen,’ Manson warned Ross. ‘I do not hear that the Germans are moving but they will and so will the Russians. Cut in first.’

  In fact, Ross was about to make a breakthrough. All his early experiments had been performed on mosquitoes of two distinct genera, Aedes and Culex. The former he called ‘brindled’, and the latter grey or bar-backed. Both types of mosquito can be a menace to man: Aedes aegypti spreads yellow fever, and was thus responsible for the single biggest problem the French encountered in Panama; Culex fatigans transmits the filarial worm, as well as various viruses that cause encephalitis. Neither, though, transmits human malaria. Ross had begun to suspect as much as his tour of duty in Bangalore was drawing to a close. Eager to see if another species of mosquito would answer his many questions, Ross asked for two months’ leave to travel to Sigur Ghat, a valley of coffee plantations not far from the Nilgiri Hills in south-western India where, by coincidence, the cinchona seedlings Sir Clements Markham had obtained in South America had been planted out nearly thirty years earlier by William McIvor.

  Instead of the right mosquito, Ross found something quite different.

  Just two days after he arrived, he fell ill with pains in his liver. Within half an hour he was seized by chills. By midnight he was delirious with fever and suffering badly from aching bones. The fever lasted two hours and then broke, allowing him to sleep. The next morning he felt better, and immediately set to examining his own blood. ‘I found only one small amoeboid body (quite typical and moving) in two excellent specimens,’ he would write to Manson two days later. ‘I don’t know the species. At 9 a.m. fever began to come on again without rigor & very slightly. I slept till 3 p.m. when I woke in much perspiration & have not had fever since. Liver still hurts on a deep breath but I gave the parasites such a warm reception with quinine that I don’t think they liked it.’

  Ever the scientist, Ross went back over every detail of the previous few days to try to work out how he fell ill. He had slept at night under a mosquito net ‘and with closed windows & doors’, and had religiously drunk only boiled water and milk. He tried to calculate the volume of air he had breathed in since arriving in the malarial zone, and the number of parasites he might have ingested through drinking cool tea; but neither of these suggested themselves as a plausible cause of his illness. Manson, once he’d expressed his sympathies, was patently delighted that Ross appeared once more to be concentrating on the job in hand. ‘I am very glad to hear the Plasmodium is to the fore again,’ he wrote, ‘and that you will be on his tracks so soon. Stick to him. Sooner or later he will do much more for you than sanitation work in Bangalore.’

  Manson’s enthusiasm notwithstanding, Ross continued to fret about how he could have caught malaria. He continued to go through the possibilities, slowly casting each one aside. The water and milk he had poured into his tea had been boiled, so there was little chance of having swallowed an infection. The air he had breathed could not have been full of parasites: Ootacamund, where he had left his family before setting off for Sigur Ghat, was not especially malarial – certainly not enough for parasites to be present in the air in large quantities.

  Only l
ater did Ross remember that in between leaving Bangalore and arriving at Sigur Ghat, he had visited the damp bottom of the ghat proper, ‘and spent the whole day there hunting for mosquito pools and examining dew puddles’, which were a well-known source of malaria. If anything led him to abandon Manson’s theory about drinking in malaria from dead mosquitoes, it was the personal observation of his own sickness: ‘Another five days in the jungle reversed the position of affairs in favour of the mosquito theory but only just as I was beginning to give it up,’ he wrote to his mentor.

  If Ross had caught malaria in an area where mosquitoes abounded, and where much of the human population carried the Plasmodium parasite in their blood, then surely this must mean that mosquitoes not only sucked up infected blood, but also passed it on. And when could they possibly do that, other than while biting a human? Mosquitoes were not, as Manson believed, simply a transport system that carried the plasmodium around within the environment. Nor were they, as the Italian malariologists believed, like living syringes, inoculating people as they bit them. Rather, the mosquito proboscis was a dual carriageway, a passage in both directions, in and out. To accept this meant abandoning the conventional view, long clung to by Manson and others, that the malarial germ somehow just hung about in the environment, which was not something Ross was quite ready to do yet. But he was getting there.

  There was nothing to warn Ross that 20 August 1897 was to be a remarkable day in any way. By now he was back in Secunderabad, and hard at work despite the heat and the presence of colleagues whom he found irritating – ‘bachelors, half-castes, men with huge families & lazy men’, as he had described them in a letter to Manson a month earlier – pressing on with dissecting the brown mosquitoes in search of a sign, any sign, that might prove they carried the malaria parasite. ‘Unfortunately it turned out that my mosquitoes were very few in number,’ he would recount to Manson, ‘but they bit well and kept well.’

  Although Ross tries in his letters to maintain the calm objectivity of one scientist communicating with another, his palpable excitement begins to shine through. Victorian he might have been, but he would have been inhuman if it didn’t. ‘I dissected the first [mosquitoes] without any result,’ he began.

  On Friday 20th I had only two left. One of [these] was very carefully dissected. I noticed at once some cells in the stomach rather more distinct than the usual very delicate stomach cells. The outline was sharp but fine and not at all amoeboid, the shape spherical or ovoid, the substance rather more solid than that of the neighbouring cells. Now I am so familiar with the mosquito’s stomach that these bodies struck me at once; and you may imagine how much more struck I was when, on focusing carefully I found they contained pigment …

  It was black or dark brown (not blue, or yellow or greenish … Now what do you think of this? Examining next day, the cells, as I expected they would … showed up more clearly and could now be made out easily … The pigment had clustered more into clumps. In fact, apart from the pigment, the bodies looked parasitic …

  On the 21st I killed my last brown mosquito and rushed at the stomach. The very same bodies(!) only larger, more distinct with thicker, perhaps double, outline (sometimes).

  As he worked, Ross began making an inventory of his findings, knowing that if he jumped too soon to conclusions others in the field would be only too quick to shoot him down. ‘Hence we have (provisionally),’ he wrote, ‘1) The pigmented cells [that] appear to exist in malariated brown mosquitoes but not in brindled ones; 2) they are larger on the fifth day than on the fourth day; 3) they occupy only one part of the stomach; 4) they become more distinct under formaline; 5) they are sometimes intracellular, and 6) they have pigment exactly like that of the malaria parasite.’

  Ever since Laveran had identified the malaria parasite seventeen years earlier, precisely by identifying the dark colour that appeared within the haemamoeba, the old name he used for the red blood cells he examined under his microscope, ‘pigment’ – it is the same word in French – had become a magic word, the Eureka of the study of malaria, a proof of knowledge and the key to advancement within the field.

  ‘The remarkable thing about them,’ Ross wrote to Manson of the dark cells he had found within the mosquito’s stomach, ‘is undoubtedly the pigment. I have never seen this before in any mosquito (I have now examined hundreds – or a thousand). It always lies in the cells and is not scattered outside them or in any other cells. In short it is as distinctive a feature of them as it is of the haemamoeba. No other bodies but these two that I have ever seen contain such pigment; and it is the same exactly in both. Wait now. You will say at once (as I used to think) that the parasite in the mosquito cannot have pigment, because this is known to derive from haemoglobin, and the mosquito has no haemoglobin. Has it not though? Why its stomach is full of it … Anyway there’s the pigment, just like what we see in our old friend. Two points must be proved,’ he concluded, looking ever ahead, ‘a) that the cells are parasites; b) that they are malaria parasites.’

  Ross left a few days later to pay a visit to his long-suffering wife Rosa, whom he had left in Ootacamund. He carried with him a set of mounted specimens showing his ‘wonderful pigmented cells’. While there he wrote a short note to the British Medical Journal, then as now one of the most august scientific journals of the day. With the warning Manson had given him about foreign competition fresh in his mind, Ross was anxious to publish his discovery in case someone else ‘happened to hit on the right species of insect [and] polish off the whole business’. His paper, quietly entitled ‘On Some Peculiar Pigmented Cells Found in Two Mosquitoes Fed on Malarial Blood’, was published in the last issue of 1897. The study of malaria had been changed forever.

  Ross had been reticent about the importance of his findings in his paper, but Manson, who had forwarded it to the BMJ on his behalf, attached a short but enthusiastic note: ‘I am inclined to think that Ross may have found the extracorporeal phase of malaria.’ In private, and to Manson in particular, Ross was more excited: ‘I really believe the problem is solved, though I don’t like to say so … I have hardly restrained myself from wiring “pigment” to you, but fear you would think I had gone mad. Well I know pigment by this time. I am on it.’

  Indeed, Ross felt so ‘on it’ that at the end of his historic day, even before he wrote to Manson, he turned again to poetry, writing in his small notebook:

  This day relenting God

  Hath placed within my hand

  A wondrous thing; and God

  Be praised. At His command

  Seeking His secret deeds

  With tears and toiling breath,

  I find thy cunning seeds,

  O million-murdering Death.

  I know this little thing

  A myriad men will save.

  O Death, where is thy sting,

  Thy victory, O Grave!

  Ross was convinced that the final secrets of the transmission of malaria would soon be his. Perhaps it was this that tempted him to overlook the fact that although he had observed the snaky flagella that were so characteristic of the parasite in human blood, and had found the parasite developing within the mosquito’s stomach three days later, he had no clearer idea—in fact, no idea at all—about what happened during the intervening period.

  His unwillingness to recognise that this opened a gap in his theory also led to a certain reluctance to look around and see the true worth of the work being done by malariologists in other countries. Some, such as W.G. MacCullum, a medical student who lived outside Toronto, were, like Ross, scientists working alone with meagre resources. By contrast, Giovanni Battista Grassi, Amico Bignami and Giovanni Bastianelli worked in well-financed and well-respected departments within the medical establishment of Italy – the country that was, for many, still the heart of malaria studies, even though Italians were no longer making groundbreaking discoveries at the rate they once had done. Ross, chippy and insecure, was immensely proprietorial about his work. He found it hard to share at the be
st of times, and even harder to acknowledge how science often moved ahead in tiny incremental steps rather than huge leaps, with each scientist adding his or her own small stone to the main wall that had already been built by others. Ross’s was a jealous nature, and this shortcoming would have serious repercussions later on.

  Just as Ross’s own work would later inspire others, MacCullum’s research had a significant impact on Ross’s thinking about how to study the transmission of malaria. MacCullum had spent the summer of 1896, the year before Ross’s journey to Secunderabad, studying the Halteridium parasite in swamp sparrows, blackbirds and crows. He found the specimens he made from avian blood contained huge numbers of parasites that were relatively large and thus easy to observe.

  In the late spring of 1897, sickness was reported among the crows of Dunnsville, Ontario. MacCullum, who was in the area, saw that the sick birds had ruffled plumage, a queer croak and an unnaturally quiet air about them. He tried to shoot one without killing it, so that he could draw blood from it while it was alive, but to no avail. Then he heard of a boy who was looking after two sick crows as pets. MacCullum leapt onto his bicycle to visit him.