'A moving target'

Interview with Elena Levashina on the state of malaria research on World Malaria Day 2019

April 25, 2019

More than 120 years have gone by since the first demonstration of the connection between mosquito bites and malaria infection. Malaria, one of the deadliest infectious diseases in the world, is now mostly present in the sub-Tropical countries in Africa, Asia and South America. New technological advances are now promising a solution in the form of genetically manipulating entire mosquito populations. But do we know enough for such massive interventions to take place?

In this interview, Elena Levashina, Group Leader at the Max Planck Institute for Infection Biology in Berlin, explains how she combined laboratory and field studies in her research to paint a comprehensive picture of the spread of malaria.

Dr. Levashina, how does an infection biologist go from the laboratory to field research?

Thanks to our laboratory studies, we knew that mosquitoes possess resistance genes that are very efficient at eliminating the malaria parasite in the laboratory models of malaria infections. But then we asked the question: does our laboratory research really reflect what happens in nature? It is complicated to breed mosquitoes in the lab and to infect them with malaria. In nature, there is no need for external intervention - it just happens. So, together with our collaborators in Mali we designed a field study that let nature do the work for us.

You have already published first results from this field study. What did you discover?

My team spent two rainy seasons - 2014 and 2015 - in Mali collecting and analyzing mosquitoes on an almost daily basis. Of course, that was time-consuming but offered an important breakthrough as previous similar studies mostly collected mosquitoes weekly or monthly. With our closely spaced time-series, we developed a completely new approach in malaria research.

Markus Gildenhard, a doctoral student from my team, came up with an idea to implement a method used in economic sciences for the data analysis. This method, called Granger causality, requires very dense time-series collections that are easy to gather at the stock market. The advantage of this method is that it tests for causal relationships between two variables. This approach has never been applied in epidemiology or vector biology, although both disciplines seek to predict the spread of infections. When applied to our data, the Granger causality test enabled us to predict abundance of the malaria parasite in a local mosquito population using a mathematical model. A high number of infected mosquitoes represents an increased risk of transmission to humans. We demonstrated that the malaria parasite abundance was disproportionally distributed between two sister mosquito species that have both previously been considered dangerous vectors.

What was working in Mali like for you?

Prior to this project, we had already collaborated with the researchers from the University of Bamako in Mali. That was a great advantage for us as they have an outstanding experience in the field work and engage the people living in the villages at the collection site. For example, we needed power for our mosquito traps. In the end, the villagers kindly shared their solar panels to recharge the trap batteries along with their mobile phones.

In order to analyze the collected mosquitoes, we also worked with the University of Bamako to set up a genotyping laboratory. This resulted in two Master’s and two PhD theses on the Mali side alone.

Ultimately there were some throughput limits, that is why we developed a genotyping pipeline in Berlin. We are currently finishing the genotyping of our 17,000 mosquito samples.

How does it feel after all the collecting to be sitting on such a huge treasure trove of data?

Firstly, it's a little frustrating. You want to analyze everything as fast as possible, you want to know what information the data will provide. But,of course, genotyping of such dense collection sets takes time. But once processed, the collected samples can be used to answer many more questions than we planned initially.

I find it particularly exciting to apply lab knowledge to design field experiments and see that this knowledge is actually valid under natural conditions in Africa. I remember Markus being very excited when he analyzed the data from the first rainy season. It seemed too good to be true and he did have strong doubts at first, and pushed for further controls. But when the indicator recurred in the second rainy season, it became clear that what we were seeing did actually correspond to reality.

What can we learn from this for the fight against malaria?

The current strategies for fighting malaria mosquitoes are relatively old. Mosquito nets and insecticides are very successful but do not reach or are similarly effective in every malaria-endemic region. Mosquitoes are continually developing resistance to insecticides; these toxins also pose a problem for the environment. 

The latest trend in mosquito control places big hopes in gene technology. Genetically modified mosquitoes are currently being developed for distribution at the malaria hot spots. The purpose of these mosquitoes is to pass on infertility genes or introduce factors reducing the malaria transmission rate into the populations. These approaches are still mostly conceptual, only a work in progress, but in addition to their effectiveness, they also promise improved environmental sustainability, as only a specific mosquito species is targeted.

You have identified more precisely the genetic makeup of mosquito species that transmit malaria in Africa. With which mosquito species would we have to start?

In most regions of Africa, there are several mosquito species living together, that can transmit malaria parasites. If we know which species actually causes parasite abundance and plays a key role in the local transmission of the disease - and that is exactly what we can understand with our model - then we should target this species. Anopheles gambiae, the species relevant to the abundance of the malaria parasite in our research, is very difficult to breed. Genetic work focuses predominantly on Anopheles coluzzi. This species is considerably easier to work with in the laboratory, but it is, apparently, not as relevant for malaria parasite transmission in West Africa as previously thought. In simple terms: at the moment, the developers of genetically modified mosquitoes are currently working with the wrong mosquito species. However, more studies are needed to identify super vectors in the major ecological settings in Africa.

What fascinates you about malaria research?

I found infection biology fascinating, even way back during my school days. Initially I thought that the romantic days of the discipline were already over. Researchers have had discovered the causative agents of major infectious diseases; it was already well known that malaria is caused by Plasmodium parasites that are transmitted by Anopheles mosquitoes.

But then I began to ask myself more questions. I noticed that we lack a precise understanding of the interactions between the mosquitoes, parasites and humans and the role of environment in these interactions. Even 120 years after the discovery of these relationships, we still face the same problems in combating the disease.

Malaria remains a moving target. Our understanding of the illness is growing, however. If we combine both the laboratory and the field studies in our open thinking, we can take the research to a new level. However, it is important to strive for a jump in our new understanding instead of reformulating curresnt approaches.

The interview was conducted by Christian Denkhaus.

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