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75th stories: Beautiful creatures – Ralph Lainson and his parasites

2 Jun, 2011
Ralph Lainson

Ralph Lainson

To mark the 75th anniversary of the death of Henry Wellcome and the founding of the Wellcome Trust, we are publishing a series of 14 features on people who have been significant in the Trust’s history. In our sixth piece, Trust Online Editor Mun-Keat Looi looks at parasitologist Ralph Lainson, the Trust’s longest-serving grantholder.

In 1965, Ralph Lainson left London for Brazil with a three-year Wellcome Trust grant. He never came back. What was it about sun-soaked Brazil that appealed to the young man? The parasites, of course.

“I’ve always said to young Brazilian students what a wonderful place they’re in. If you turn over a stone you’ll find four new species underneath it,” enthuses the 84-year-old scientist. “The Amazon region is a veritable mine of parasitological information, yet very, very few people were engaged in parasitological studies in this region when we started our work.”

It was this passion for the microscopic world that drew him to the tropics some 50 years ago. And it has resulted in a string of achievements: Fellow of the Royal Society, Officer of the Order of the British Empire, and being the Wellcome Trust’s longest-serving grantholder – a record 47 years and counting. The titles seem incongruous with this modest man who delights in telling me strange-but-true stories of the anaconda that killed and swallowed a visiting dentist on his fishing holiday, and the angler attacked by piranhas while clearing his boat’s propeller. Yet Lainson is a leading authority on parasites, particularly protozoan (single-celled) parasites. The clues are in his sand-fly-patterned tie and the joy on his face when I ask about his speciality, the neotropical parasite Leishmania.

Leishmania causes leishmaniasis, one of the most devastating diseases for low-income countries. Of human diseases caused by a parasitic protozoan, it is second only to malaria in its impact on public health: 12 million people are thought to be infected worldwide, and there are around 1-2 million new cases every year. Cutaneous leishmaniasis causes disfiguring ulcerated sores on the skin, with the added social stigma that results. In visceral leishmaniasis, the parasite attacks the internal organs, leading to severe anaemia, fever, swelling of the liver and spleen, and death within a few years if the disease remains untreated.

The parasite is transmitted by blood-sucking phlebotomine sand flies and develops in different mammalian hosts. In Brazil, this makes it a very difficult disease to control, says Lainson. “With cutaneous leishmaniasis, the reservoirs are the wild animals of the forest. With visceral leishmaniasis, wild foxes are important, but dogs are also commonly infected, forming a major source of infection for humans. And Brazilians have a very strong feeling for their dogs – ask them for blood samples and they’d prefer to offer you their children rather than their dogs!”

Lainson’s long relationship with the parasite began in Belize (then British Honduras) in 1959. His aim was to find the source of cutaneous leishmaniasis, known locally as ‘Chiclero ulcer’, and the first step was to find the parasite’s animal reservoir in the wild.

“We had the parasite isolated from humans and knew that most of the people who acquired the disease worked in the forest, often for long periods,” he recalls. Chicleros – men collecting latex to make chewing gum – spent up to six months living in the forest, so the researchers reasoned that some animal there must be harbouring the parasite. For two years they tracked all manner of creatures with little success, until a natural disaster lent a hand.

“Belize has a cycle of hurricanes every ten years and Hurricane Hattie I’ll always remember,” says Lainson. “It was a terrible experience, causing over 400 deaths and levelling flat a lot of the forest. But the result was that the wild animals became desperate for food. After that we had no problem trapping a large number of rodents, opossums and other animals in our baited traps.”

Among them was a rodent with small lesions on its tail. (As it happens, this was “the only part of the body that you could take material from easily without killing the animal,” recalls Lainson.) From these he prepared stained smears and when he examined the slides under the microscope, lo and behold, there was the parasite.

Knowing now to look at the tails, his team identified three different species of rodent that often carried the parasite. The next step was to find the insect vector that was transmitting it to humans. In the Old World, Leishmania is transmitted by phlebotomine sand flies, so it was reasonable to suppose that the vector in Belize was from the same group of blood-sucking insects.

The researchers captured large numbers of flies at night, using themselves as human bait (“You can’t do that these days,” sighs Lainson). The team fed 320 sand flies on the large skin lesions of hamsters infected with Leishmania mexicana. Of those, 52 were then fed on human volunteers a few days later. The volunteers included the team’s entomologist, John Strangways-Dixon (who told Lainson: “They’re my sand flies, so if they’re going to feed on anything or anyone it’s going to be me. I’m their boss!”).

As it turned out, Strangways-Dixon was the only case where transmission was achieved. The fly (identified as Lutzomyia passoana) bit him on his stomach and, 17 days later, he developed a small lesion. Smears made from the papule contained abundant L. mexicana. It was the first experimental proof of transmission of a neotropical Leishmania species to man by the bite of a phlebotomine sand fly.

Eventually, nine human-biting species of sand fly were found to be susceptible to infection with L. Mexicana – all potential vectors for transmitting the disease.

“It was all very exciting,” says Lainson. “We had the final experimental proof that phlebotomine sand flies are also vectors of New World species of Leishmania. When the sand fly fed on the lesions of rodents it became infected, and when it next took a blood meal from a human it transmitted the parasite to that person. Having shown this, we began to feel we were on the way to becoming scientists.”

New World order

After Belize, Lainson returned to the UK, but soon pined for the tropics. “Stuck in the London fog, I thought that, now armed with the knowledge gained in Belize, we might we able to throw some light on the reservoir hosts of L. braziliensis and, who knows, show that it is not the only parasite causing cutaneous leishmaniasis in Brazil.”

So, in 1963, Lainson toured Latin America collecting strains of Leishmania while sizing up different research institutes. He went through Central America, down to Colombia, Venezuela and elsewhere until his final stop, the Instituto Evandro Chagas in Belém, part of the Amazon delta of north Brazil.

There, he showed the researchers his photographs of rodent lesions in Belize. One of them, Dr Otis Causey, said he had seen similar lesions on the tails of Oryzomys capito, a rodent common in the region. He had thought they were simply bacterial or fungal infections growing on damaged tails.

Two weeks later, Causey approached Lainson at a scientific meeting in Rio de Janeiro, carrying a slide made from a rodent in Belém. “It was teeming with Leishmania parasites,” says Lainson. “We had for the first time found a reservoir host of at least one more Leishmania species, other than L. braziliensis, infecting humans in north Brazil.”

Lainson was among a number of scientists certain that different leishmanial parasites were involved in the disease in different parts of the continent and most probably in Brazil. Although cutaneous leishmaniasis manifested itself in different forms in Central and South America, many clinicians thought they were all due to the same parasite, L. braziliensis, and some even suggested that the parasite was the same as L. tropica, a cause of cutaneous leishmaniasis in the Old World. But some facts didn’t sit right. For example, researchers had classified a Leishmania species in the forest of neighbouring French Guyana, naming it L. guyanensis. Meanwhile, researchers had classified and named other species of Leishmania in various Latin American countries that clearly differed from L. braziliensis, both biologically and in the form of the disease they produced in laboratory animals and humans.

Forest rodent

A forest rodent, Oryzomys capito, with lesions from Leishmania amazonensis showing on its tail.

In 1965, Lainson arrived in Brazil with his colleague Jeffrey Shaw and a three-year Wellcome Trust grant, determined to clear up the confusion. His Anglo-Brazilian team collected parasite samples from many different types of animals, including armadillos, opossums, foxes, porcupines and monkeys. They also collected samples from patients with cutaneous leishmaniasis and mucocutaneous leishmaniasis – another form of the disease that arises when the parasite infects the nose and throat.

Their findings were striking: the parasites found in the rodent Oryzomys were clearly much larger than the L. braziliensis from humans, which has tiny amastigotes measuring only 2-3 micrometres in diameter; those found by Causey were up to 5-6 micrometres. The rodent parasite grew easily in culture, whereas L. braziliensis struggled to grow in the same medium. And when they inoculated the rodent-derived parasite into hamsters it produced huge tumour-like lesions in the skin very quickly, whereas L. braziliensis took six months or more for a tiny lesion to appear.

Lainson’s team found a small number of patients infected by the same parasite as that from Oryzomys, which they named L. mexicana amazonensis. In the following years they identified a (still-increasing) number of different Leishmania species, often with specific or closely related sand-fly vectors and different wild animal reservoirs. By 1979, so many Leishmania species had been discovered – 13 from the Americas at the time, eight of which infected humans – that the researchers proposed a new classification of them. Lainson has speculated that, “considering the remarkable number of Leishmania species that have now been recorded in the Neotropics, and particularly in the Amazon region, this area might well be the birthplace of this genus”.

These findings have helped to define outbreaks of the disease in the region, with considerable public health implications. People infected with L. amazonensis may develop diffuse, anergic cutaneous leishmaniasis (affecting people whose immune systems are incomplete) – a condition incurable at the time. Those infected with L. braziliensis stand the risk of developing mucocutaneous leishmaniasis, which can be disfiguring and requires prompt and particularly intensive treatment. Moreover, people immune to one species of the parasite are usually vulnerable to others, complicating vaccine production. And Brazil’s increasing urbanisation and population movement has meant that groups are often exposed to different species – and the different sand flies that transmit them – as their environment changes.

“One by one, over 30-odd years, we were able to show that there is not just a single parasite causing human cutaneous leishmaniasis, but at least seven,” says Lainson. “These are now known, identified and recognisable such that people can tell which species of Leishmania the person is infected with. Every bit of knowledge gained regarding the ecology, epidemiology and distribution of the different species is of help in attempts to control the diseases they cause.”

Beginnings

During his career, Lainson and his collaborators have described hundreds of new species of protozoan parasites (102 in Brazil alone). He has even had one named after him: L. (Viannia) lainsoni, discovered in 1987. His efforts have earned him the Chalmers Medal (1971) and Manson Medal (1982) from the Royal Society of Tropical Medicine and Hygiene, among a string of awards for services to parasitology in Brazil. Lainson tells me of his pride as an elected Fellow of the Royal Society (“the finest appreciation that anybody can give a scientist”) and receiving the OBE from the Queen in the name of science (“footballers and pop singers may be knighted, probably because they’re very useful economically – a scientist is usually underpaid and usually not very much appreciated by the majority of the population”).

He is a classic scientist, endlessly curious and obsessed with details, which is exactly how his love affair with the parasitic world began, far from the tropics on the rivers of Sussex. “I was fond of fishing, as was my father,” says Lainson. “He said to me, ‘the first fish you catch, cut it open, look in the intestine and the stomach, and see what the fish is eating. Then you’ve got an idea of what bait to use’. When we did this I was intrigued by a number of white worms that were wriggling around. I asked, ‘what are these, dad?’ And he said, ‘well, they’re parasites’.”

“I was fascinated by the thought that some parasites were only a few micra in size and only one cell at that. I found it quite extraordinary that we could look at these things with a microscope – that scientists could see a trypanosome, for example, moving about in the blood of an animal.”

Returning from the army after World War II, he read biology at the nearby Brighton Technical College (what would later become the University of Sussex). A PhD at the London School of Hygiene and Tropical Medicine followed, and there the young Lainson met the man who would literally set him on course for a new world: Professor Cyril Garnham.

In Lainson’s words, Garnham was “one of the few remaining traditional parasitologists, whose passionate interest centres on parasites themselves rather than the disease they might cause…He was sure that he was going to make me into a scientist whether I wanted to be or not.”

One day, the Professor called his young protégé into his office. “He said to me, ‘Lainson, you can’t learn anything about tropical medicine in London, you’ve got to go to the tropics.’” Garnham arranged for Lainson to go to British Honduras to work on the epidemiology of leishmaniasis. “He had a very dry sense of humour. I was a bit disappointed with the low salary, and he said, ‘Oh Lainson, you needn’t worry, there are all sorts of bush meat you can eat. I understand that the iguana tails are very nice…’”

Lainson’s long association with the Wellcome Trust stemmed from the same Rio conference at which he met Otis Causey. There he also met an associate of the Trust, which led to an introduction to Sir John Boyd, a Wellcome Trustee and a famous name in tropical medicine (he was President of the Royal Society of Tropical Medicine and Hygiene). Recalls Lainson: “I’d taken lots of photographs of leishmaniasis on my travels and showed these to Sir John. He was so impressed by the horrific pictures he said, ‘We really need somebody working on this disease’, and I got a grant from the Trust with no trouble at all.”

Further serendipity followed. Shortly before he departed for Brazil, he met another of Garnham’s students. Fresh off the boat from Panama, Jeffrey Shaw had just obtained his PhD working on the Endotrypanum parasite, which lives in the red blood cells of sloths. He had discovered that it was transmitted by sand flies, just like leishmaniasis. But it was the lesion on Shaw’s neck that first piqued Lainson’s interest. “I asked what it was and he said he didn’t know. He’d been to one or two doctors but they couldn’t help. It looked to me very much like cutaneous leishmaniasis, so I took a scalpel, made a smear, stained it and there were amastigotes of Leishmania.”

From this coincidence, a prosperous scientific partnership was born. In 1965, Lainson and Shaw began a three-year mission to unpack the complex interactions between the parasite, insect, wild animals and humans involved in Brazil’s cutaneous leishmaniasis. Three years turned into 30 and their research group became the Wellcome Parasitology Unit.

Under Lainson’s directorship, the Unit made a string of important discoveries in leishmaniasis and other parasitic diseases. In 1969, they published the first record of Chagas’ disease in the Amazon region of Brazil, demonstrating that it could spread easily through food contaminated with faeces from species of blood-sucking triatomine bugs – the vectors of the trypanosome parasite that causes this disease. In 1977, they published in ‘Nature’, describing the first experimental transmission of Leishmania chagasi (the cause of American visceral leishmaniasis) by the bite of the sand fly Lutzomyia longipalpis. And in 1981, the Unit discovered a new sand fly transmitting Amazonian cutaneous leishmaniasis, which they named Lutzomyia (Psychodopygus) wellcomei. Says Lainson: “We have an expression in Portuguese: pucha saco, which means that by giving it this name, we might persuade the Trust to continue our grant!”

Although the Unit closed in 1992, its legacy continues at the Instituto Evandro Chagas, now a hub for visiting scientists researching all aspects of Leishmania and other parasites, from ecology to epidemiology, immunology and the genetics of host responses to infection. It also boasts a significant resource in its collection of cryo-preserved parasite material and records, amassed during the Wellcome Unit’s life. Lainson says: “A Brazilian clinician once said to me, ‘we think of leishmaniasis in terms of before the Wellcome Unit and after the Wellcome Unit’. Leishmaniasis was a very poorly studied disease, and is still referred to as one of the neglected diseases by the World Health Organization. But at least we now know that its cause in Brazil is not just one parasite, but several!”

He speaks about Leishmania with a sense of wonder: “It’s extraordinary that Leishmania has selected the macrophage – a cell whose purpose is to destroy any invading organism – in which to divide. Extraordinary.” And though he ‘retired’ in 1996, Lainson hasn’t left the lab. Fourteen years later, he still spends his spare time staring down a microscope, addicted to finding out more about the protozoan parasites of the Amazonian fauna.

He’s anxious that such work should continue, particularly research on ‘neglected’ parasites that are not of mainstream medical interest. His current project is an atlas of every parasite discovered in the Amazon region over the last 45 years, many by himself and the Wellcome Unit. The Instituto Evandro Chagas will be producing three volumes: one on Leishmania species and trypanosomes, one on miscellaneous parasites of fish, frogs and birds, and another on Lainson’s other parasitological passion: parasites in the blood of lizards and other reptiles.

“I am most proud of the work that we did on Leishmania, because of its great importance in medicine,” he says. “But I also feel pride in the fact that we have described almost 100 new species of protozoa parasites in a whole range of animals from the Amazon region, including seven new species of Leishmania. And I take pleasure in the fact that we’ve described a whole new family of malarial parasites in wild lizards that were hitherto unknown. I think of myself not as a leishmanologist but as a parasitologist.”

“What I love about my work is the opportunity to discover and enjoy the extraordinary beauty of structure and complicated life cycles of these little organisms. It’s not work, more of a very interesting hobby, and these parasites are rather beautiful little creatures.”

Find out more about activities marking the Wellcome Trust’s 75th anniversary, including links to other features as they are published.

Image credits: Wellcome Images, Ralph Lainson
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