Making Drugs to Fight Malaria

The term ‘vector-born disease’ refers to infections that are transmitted from one animal to another by a vector. These vectors are usually small blood-sucking organisms such as insects and alike. And yes, perhaps the most annoying blood-sucking insect known to mankind- the mosquito, is also a major vector for many diseases. Malaria, Chikungunya, Dengue, Yellow Fever, Zika and many other diseases are transmitted by mosquitos. Generally, these diseases are transmitted when a mosquito bites one infected animal (e.g. a human that has the malaria parasite in his/her blood), takes up the parasite with the ingested blood and then injects this parasite to the next person as it takes a subsequent blood meal. In the case of malaria, the parasite a mosquito transmits belongs to Plasmodium genus. Plasmodium parasites replicate in liver and red blood cells of the infected hosts and cause these cells to burst and die. Recurrent bursts of parasite growth in red blood cells are what leads to the waves of high fever, which is a typical symptom of malaria.

False-colored electron micrograph of a Plasmodium
False-colored electron micrograph of a Plasmodium

Malaria as a disease has been known for thousands of years, references to malaria-like symptoms can even be found in the writings of Hippocrates. Scientific studies on malaria have started in the second half of the 19th century, however, the disease still has a significant global burden. In 2015 around 214 million people had malaria and 430 thousand people died from it. It is not all doom and gloom though, global efforts to prevent and treat people from malaria managed to almost half the total number of deaths from malaria since the year 2000. Especially preventative measures such as bed nets and pesticide spraying to kill the mosquitos have been and still are highly successful. And while there’s still no vaccine on market, artemisinin, a drug used to treat malaria infection, is very effective. In 2015 one half of The Nobel Prize in Physiology or Medicine was awarded to Youyou Tu, a scientist who discovered artemisinin. In 1970s Youyou Tu was going over old texts describing various herbal plants that were used to treat malaria in traditional Chinese medicine. Amongst many plants she found Artemisia annua, a sweet wormwood, from which she went on to extract the active component, named it artemisinin, and showed that it can be effectively used to treat malaria in animals and humans. Artemisinin is still used globally in combination with other antimalarial drugs (called artemisinin-based combination therapy), however, artemisinin resistant strains of Plasmodium have been identified in a the Greater Mekong Subregion and they highlight the need for discovery of new drugs.

As for artemisinin itself, almost 100 tonnes of it are needed each year to treat malarial infections, however, there are still great challenges in finding cost-effective ways of producing artemisinin. The main way of producing artemisinin used to be by extraction from Artemisia annua plant itself, however, the costs of growing the plant and the efficiency of the process (5 kg or artemisinin per 1,000 kg of dried leaves) has never been sufficient to meet the global demands. Therefore, the producers have now focussed on looking for new synthetic ways of making the drug. With a financial backup from Melinda and Bill Gates foundation a company called Amyris and its collaborators have created a yeast strain capable of making artemisinic acid (a precursor for artemisinin) in fermentation reactors at relatively high yields. Even so, the cost of producing artemisinic acid in yeast is still quite high making it difficult to obtain for the poorer countries in Asia and Africa, which are usually most afflicted by malaria.

Artemisinin production
Artemisinin production

In the view of the need for better ways of producing artemisinin a recent study presented in journal eLife has described a tobacco-plant based production of artemisinic acid. In a previous blog I’ve mentioned that flu vaccine components as well as an antibody used to treat Ebola virus infection have been made in tobacco leaves, so production of artemisinin in tobacco is not an outrageous idea. To make any kind foreign component in a plant (that is something that is not normally made by the plant’s cells) one firstly needs to introduce the genetic information, which codes for that component, into the plant. Making artemisinic acid in tobacco, however, is quite challenging because its production is not a single step process, which means that a number of different genes need to be added. Moreover, perhaps one of the most difficult parts of putting foreign pathways into cells is that the control of their components is often disrupted leading to non-functional or inefficient expression of the proteins of interests. In the eLife study scientists have made number of different gene constructs that code for artemisinic acid production pathway and put these into tobacco plants. Most constructs could lead to artemisinic acid production in the leaves, however, unbalanced production of some of the components in the pathway led to stunted plant growth, something that has to be considered when thinking about efficiency of producing the drug on a market scale. Ultimately, optimising constructs and screening for additional genes which could potentially improve production steps led to generation of tobacco plants that could produce 20–40 mg of artemisinic acid per kg dry leaf weight. So how much tobacco would the producers need to grow to meet the demand 100 tonnes per year? Authors suggest that using their best plants it would take around ~200 km^2, which is almost 8 times smaller area than London city.

Further reading:

Vector-borne diseases 

Nobel Prize

WHO malaria statistics 1

WHO malaria statistics 2

Artemisinin from microbes

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