My boyfriend and I are very into biking. Specifically, we adore long-distance tandem biking. Aside from science, it is the passion that takes up the majority of our time. In fact, we are planning a world circumnavigation by tandem bike for 2024, and we will try to break the current world record for the fastest circumnavigation by tandem bike. To prepare, we are already mapping out a route and consuming media produced by other long-distance bikers, including the movie that we watched last weekend: Kapp to Cape.
Myself and our first tandem, fully packed at the Seine in 2018
Kapp to Cape covers two cyclists undertaking the ambitious goal of making the fastest ever journey by bike from the Arctic Circle (Nordkapp, Norway) to Cape Town in South Africa. During their journey, however, a nasty microbe makes a prominent appearance: Malaria.
This microbe’s guest appearance in the Kapp to Cape film especially caught my eye because I knew that 2021 happened to be a big year in humanity’s fight against malaria. In the summer of 2021, China was at long last WHO-certified as malaria-free. After being reminded of this triumph against malaria upon my viewing of Kapp to Cape, I thought that early 2022 was a great time to look back on our history with malaria.
Malaria is truly an ancient disease, and some of the first references to it actually come out of China, from around 2700 BCE. Historical references also suggest that malaria was present and causing significant societal problems in ancient Mesopotamia, Egypt, and India. However, although the symptoms were pretty well described (such as fever and enlarged spleens), the cause of this disease was unknown for millennia. Actually, the name ‘malaria’ indicates the formerly leading hypothesis regarding the cause of this disease, which was held for centuries: “mal’aria”, or “bad air”. Until the late 1800s, even the top scientists were convinced that malarial fevers were a result of inhaling “spoiled air” in wetlands.
As the authors of this review put it, “Our understanding of the life cycle of the malaria parasites did not proceed in [a] logical order… but more like a jigsaw in which the various pieces were painstakingly put into place and, like a jigsaw, often involved mistakes and false starts.” Part of the reason for this is that there are five different species of protozoan parasites that can cause malaria, and they all have in common a very complex life cycle spanning multiple different life stages that is rather difficult to piece together and connect. I must admit, I remember struggling to understand the cycle of the malaria parasite’s life in the last year of my B.Sc., even though I had the luxury of having all of the relevant information at my fingertips, unlike the early scientists who pieced this information together.
So what is this complex life cycle then? As I hinted at earlier, malaria is caused by five different species of the Plasmodium parasite, which all have a similar but mind-boggling life cycle. If you ever meet a Plasmodium, you will first meet it as a “sporozoite”, which is describes a sort of teenage point in the Plasmodium life cycle that can be injected into your body with a mosquito bite. These sporozoites will run about your body until they find some liver cells, which constitute the perfect environment for the next stage of the Plasmodium life cycle. In the liver, each of the Plasmodium sporozoites will mature and then divide into many different “merozoites” which then flood out of the liver and into your blood stream, where they infect red blood cells. Once inside your red blood cells, the merozoites divide again to make more of themselves. It’s actually this infection and destruction of red blood cells by merozoites which is responsible for the actual symptoms of malaria.
While wreaking havok in your blood, some of these troublesome merozoites will further develop from their asexual merozoite forms into “gametocytes”, which can be either male or and female. From the point of view of these gametocytes, the best possible outcome is for their human host to be bitten again – specifically by a female mosquito. If that mosquito sucks up some gametocytes within the human blood that it feeds upon, the gametocytes are free to ‘mate’, forming a sort of egg-like stage of the Plasmodium lifecycle, which is called an “ookinete”. This ookinete will settle into the gut tissue of the mosquito, and eventually give rise to a new generation of sporozoites that upon their birth will swim to the mosquito salivary glands and await their injection into a new human host.
This complex life cycle was indeed not discovered all at once, but rather due to an extended and world-wide effort to discover the microbe at the root of malaria. It all started with the discovery of the blood-residing merozoites by a lone French Army officer by the name of Charles Louis Alphonse Laveran. As a physician, Laveran had access to the blood of malaria-infected officers in Algeria, where he was stationed, and he noticed curious microbes in that blood. Although his findings were initially met with skepticism, his work was soon supported by work done by the Italian scientists Marchiafava and Bignami and the Russian Vassily Danilewsky. Laveran eventually was awarded the 1907 Nobel Prize in Physiology or Medicine for his dedication to investigating malaria and other infectious protozoan microbes. Notably, this was the first time a protozoan had ever been shown to inhabit a human blood cell – previously much the focus on finding the microbial cause of malaria had been on identifying a responsible bacterium. This finding, in and of itself, represented a shift in the ideas around medical microbiology in the late 1800s.
After Laveran showed that it was indeed a protozoan parasite at the root of malaria, the stage was set for the Canadian-American team of William MacCallum and Eugene Opie to describe the gametocytes fusing into an ookinete around the turn of the century. However, it was not until 1947 when the London-based team of Henry Shortt and Cyril Garnham found that showed that before the malarial parasites appeared in the blood, they would localize to the liver.
And it was then, in the mid-1900s, that at long last women were finally permitted to participate in science, and some very smart ladies got around to finding a treatment for this deadly disease.
Keep in mind that the two women whom I want to write about today are by no means the only scientists whose work has helped humanity rid entire countries of malaria. I decided to focus in on their work nonetheless because far too often, only the work of male scientists makes it into the history- and textbooks. This is my little attempt to right that (in my opinion) wrong.
With that said, let’s start in London, with Ann Bishop. Although “Ann had to sit on the first aid box at departmental tea while the men occupied the table” at the Zoology Department in Cambridge where she began her decades-long scientific career, as far as I can tell she was unrattled and unstoppable in the lab.
Bioshop played a great role in setting the stage for future research into malaria and treatments for it, and indeed struck out to study it quite alone. In the Zoology Department where she worked, nobody else worked with, or was much interested in, protozoa. Yet, she persisted and eventually found a mentor in Clifford Dobell, then a major protist expert for the British Medical Research Council. She later worked with Dobell as his scientific assistant and even eventually honoured Dobell by naming a new genus of parasitic amoebae after him.
Bishop’s knowledge of Plasmodium became particularly important during the second world-war when quinine, the main antimalarial used at the time, became difficult to access after the capture of the then ‘Dutch West Indies’ by Japan. Finding alternative antimalarials was important for the British war effort because (spoiler!) just as in Kapp to Cape, the brutal fevers of malaria could quickly stop people in their tracks. Not only did Ann’s research directly help the war effort, but her previously published articles that outlined insights into research on malaria also helped to educate the influx of biologists streaming into the field upon being asked to join the quest to find new antimalarials to protect Allied soldiers abroad.
Aside from her work on malaria, from the documents I found, Ann seems like she was just a nice person, which is really lovely to read about. She’s quoted as saying that “she was fortunate in having colleagues whose standards were so high”, and there is an anecdote of her standing outside the early meetings of the “Parasitology Group” within the Cambridge Institute of Biology, which she co-founded, with a heavy pudding basin to collect coins to fund the meetings. Within five years, the group had grown so much that it became an independent society at Cambridge, and Ann’s summary of this occasion was, “Thus, in five years I graduated from holding a pudding basin at the door to presiding at a dinner at which the birth of the new Society was toasted.’ I can’t help but like her.
Ann, however, was not the only woman hard at work at finding new antimalarials. On the other side of the globe, Tu Youyou was performing research in China that would eventually earn her the 2015 Nobel Prize in Physiology or Medicine – just over a century after the Frenchman Laveran earned the 1907 Nobel Prize in Physiology or Medicine for his early work on Plasmodia.
Despite having no medical or doctoral degree, Youyou’s research has changed the world. Youyou studied Chinese herbal medicine, and put that knowledge to very good use when she was appointed to head a Chinese national project to develop new antimalarials in the late 1960s. Rather than starting with the most recent scientific findings on malaria as many other scientists may have done, Youyou and her team took a historical approach. They used the fact that malaria is an ancient disease to their advantage, and went back to malaria’s roots in ancient China. The team spent hours screening classical Chinese herbal medicine books to find ancient antimalarial herbal prescriptions.
One herb in particular, which was found in a 1600-year-old medical tome, stood out: “Qinghao”, or “sweet wormwood” as it is known in English. Following the instructions in this medical book, Youyou found a way to extract the active anti-malarial ingredient, which she named “Qinghaosu”, from the plant. This active compound, now known as artemisinin, has since been proven to not only indeed be a highly effective antimalarial (and Tu Youyou volunteered to be the first human subject to test this), but has also saved millions of lives and was instrumental in the recent achievement of China’s malaria-free status.
One of my favourite facts from Tu Youyou’s story, as incredible as her entire biography is, is that it seems almost to have been her fate to be the woman to successfully isolate artemisinin from the plant Qinghao. As this Harvard publication explains, “She got her name from an ancient Chinese poem that translates as ‘deer call (“youyou”) when they are happily eating the plant Qinghao in the wild.’ As unbelievable as it seems, it was a complete coincidence that Youyou’s scientific career turned out to be closely bonded with her namesake.”
To conclude today’s article, it is thanks to the hard, and intelligent, work of these men and women throughout history and across the world that more and more countries are becoming malaria-free - and my boyfriend and I won’t have to worry about this pesky protozoan parasite as we cycle through China in 2024.
Until next time, remember to do like Tu YouYou - don't just work hard, but also work smart!
~Alex
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