13 October 2020
More than one billion people worldwide suffer from devastating tropical illnesses that to date have been insufficiently researched. Biochemist Professor Ute Hellmich is exploring new ways in which these neglected diseases can be treated. Her research group employs a structural biological approach, concentrating on three closely-related parasites that causes Chagas disease, African sleeping sickness, and leishmaniasis.
"It is essential that we focus more on the many neglected tropical diseases in the world," says Professor Ute Hellmich of the Biochemistry division of the Faculty of Chemistry, Pharmaceutical Sciences, Geography, and Geosciences at Johannes Gutenberg University Mainz (JGU). The World Health Organization (WHO) has put together a list of 20 neglected tropical diseases, including leprosy, dengue fever, elephantiasis, leishmaniasis, Chagas disease, and African sleeping sickness. "More than one billion people suffer from these diseases, which are often fatal when left untreated. We in the Western world, whether in Europe or North America, forget how lucky we are that the pathogens of these diseases are not transmitted because we live in areas with such temperate climates." Mainly affected at present are populations living in the tropics in considerable poverty and in very poor sanitary conditions.
"But due to global warming, these diseases are gradually coming our way as well," Hellmich points out. "I remember it was three years ago that I first saw a tiger mosquito on our campus." Among other things, this insect is a carrier of dengue fever. The WHO estimates the annual number of infections at just under 400 million while infant mortality is high. "Actually, the neglected tropical diseases are already beginning to arrive on our doorstep," confirms Eric Schwegler. "On the one hand, these diseases can be introduced by returning travelers and by immigrants from regions where these diseases are endemic. The import of infected dogs is another potential source of transmission. Infection with leishmaniasis has, for example, occurred in many dog kennels located in Europe. At the same time, the rates of leishmaniasis infection have been increasing in the Mediterranean region for years although affected persons have not been in any of the known endemic areas. So it seems this tropical disease is already firmly established there."
Three highly efficient parasites
Schwegler is writing his dissertation on neglected tropical diseases, in particular those caused by parasites of the Trypanosomatida family. These include African sleeping sickness, Chagas disease, which is endemic in South and Latin America, and leishmaniasis, which is present nearly everywhere in the world. He not only looks at the related biochemical processes, but also considers societal factors. "Many tropical diseases lead to patient disfigurement, for example through the formation of edema or through the degradation of individual areas of skin on the face. This often results in social stigmatization of the affected person. To date, aspects like this have been only inadequately examined in medical research, especially with regard to neglected tropical diseases." Schwegler pursues this dual approach as a member of the JGU Research Training Group on "Life Sciences – Life Writing: Experiences at the Boundaries of Human Life between Biomedical Explanation and Lived Experience", funded by the German Research Foundation (DFG). The group brings together researchers from the humanities and life sciences and is headed up by Professor Mita Banerjee from the JGU Department of English and Linguistics and Professor Norbert W. Paul from the Institute of History, Theory and Ethics of Medicine at the Mainz University Medical Center.
Biochemist Eric Schwegler also belongs to Hellmich's Membrane Biochemistry group at the JGU Department of Chemistry and she is supervising his dissertation. Since establishing her team in Mainz in 2015, Hellmich has initiated several projects dealing with the trypanosomatids in question. Her projects are funded by the German Research Foundation (DFG), the German Federal Ministry of Education and Research (BMBF), and, since early 2020, through a Boehringer Ingelheim Foundation Exploration Grant worth EUR 80,000 designed to provide outstanding young scientists doing basic research in biology, chemistry, and medicine with the opportunity to explore new lines of research.
"Tropical diseases are caused by bacteria, viruses, or parasites, among other things, which are transmitted to humans and animals by insects," explains Schwegler. "These parasites are a particular challenge for us because they have had millions of years to adapt specifically to their hosts. This makes it difficult to selectively combat them in patients. We are concentrating on three parasitic pathogens that are related to each other and we hope to be able to use what we have discovered so far to fight other parasites as well – in other words, kill several birds with one stone." Schwegler displays a map with colored areas showing where the associated diseases proliferate: Trypanosoma cruzi causes Chagas disease in South and Central America as well as further north into parts of the USA, Trypanosoma brucei causes African sleeping sickness in the tropical belt of Africa, and Leishmania causes leishmaniasis in South Asia, North East Africa, and Southern Europe.
"Chagas disease is barely known in Europe," says Schwegler, "but in São Paulo there is no need to explain to anyone why you’re conducting research into it. Patients with Chagas disease fill entire hospital wings there. Everyone knows someone who has Chagas." The WHO estimates that around 7 million people currently suffer from Chagas and registered the death of 7,700 infected persons in 2016. The actual numbers, however, are probably much higher because many cases go unreported.
One World, One Health
Despite all this, the development of new therapeutic approaches is not exactly receiving priority attention at present. The designation "neglected" used for these tropical diseases says it all – they are still largely ignored in both social and research contexts. What makes this particularly evident is the fact that the few drugs that are on the market have extremely serious adverse effects. "Many of these medications are themselves extremely toxic for patients while plenty of those affected simply can't afford them. In the world of pharmaceuticals, it all depends on whether the problem is of interest to society in general – and if so, which society that is," notes Schwegler. "The question is who is affected and whether those affected can afford to pay. If not, society in general needs to ask itself whether it can afford to ignore such groups." And Hellmich adds: "The emotional concerns are not equivalent to the number of people affected. About 20 times more money has been invested in the fight against HIV, tuberculosis, and malaria than in the fight against all of these tropical diseases together."
Hellmich wonders whether the coronavirus pandemic might lead to a change in attitudes: "It shows us that we are doing the right thing working on the principle of One World, One Health. At the moment it seems that, unlike in the case of COVID-19, there is only local interest in tropical diseases, but we have since learned how quickly such outlooks can change." She is certainly thankful for the support for her projects coming from a variety of sponsors such as the Boehringer Ingelheim Foundation and the Research Training Group on "Life Science – Life Writing", but Hellmich herself is to some extent surprised by the level of interest in the subject. "We are also collaborating with research groups in Pharmaceutical Sciences and Organic Chemistry. This should help us achieve a breakthrough."
Essential enzymes as therapeutic starting points
The starting point for Hellmich's and Schwegler's research was Trypanosoma brucei, the parasite that causes African sleeping sickness. "We are interested in one essential enzyme in this unicellular organism that does not occur in humans and animals, something called tryparedoxin," explains Schwegler. "The enzyme protects the parasite from oxidative stress and promotes its proliferation. If we switch off the enzyme, the parasite dies." When working on his Master's thesis in the Hellmich group, Schwegler already collaborated with organic chemists Professor Till Opatz and his Master's student Marco Preuß to optimize the effects of a known enzyme inhibitor. Now they aim to transfer the insights they gained to dealing with the related parasites Trypanosoma cruzi and Leishmania.
"Actually, it happens time and again that effective drugs are discovered by chance," states Schwegler. In fact, it is not uncommon that it remains a mystery as to exactly why or how an active substance works. On top of that, there are often unpleasant adverse reactions that accompany the beneficial effects. Discovering a cure is rather like a shot in the dark. "But with the help of structural biology, we should be able to create a rational design. It is our objective to grasp the underlying processes in detail and stay focused on the outcome we want." – "In order to improve our chances of disabling the parasites and better understanding their biochemistry, we won't be limiting our investigations to tryparedoxin alone. We are also looking at other proteins that are essential for the parasites, but which either do not occur at all in humans, or function or are structured in a significantly different way," adds Hellmich.
In its research into neglected tropical diseases, however, the research group is not exclusively concerned about the practical applications of its findings. "In our field, we also find these parasites highly interesting from a purely biochemical perspective. They represent a fascinating model system of cellular biology," asserts Hellmich. "In fact, what we are doing is basic research. That means we can look at things without directly drawing benefits from the findings. In a way, this is a luxury that the university allows us. But it is also exactly what brings science forward over long term."