Why Chagas' Disease matters

Chagas’ Disease, or American Trypanosomiasis, is one of the world’s most extended lethal parasitic infections. It is also the main cause of heart failure in Latin America. Around twenty million people are already infected, and each year this figure increases by fifty thousand. The population living in areas of infectious risk is around one hundred and twenty million people, roughly a quarter of Latin America’s population.

Despite all these facts this disease remains unattended because its insidious nature, although its mortality rate is high, it kills years, and even decades after the infection, frequently from heart failure, which figures in registrations as the official cause of death, eclipsing the role of the disease and diminishing its importance in the official registers. Often the person remains impaired during the last years of his life, unable to do any physical labour. In an urban environment this would not be a problem, but most of the affected live in rural areas, dependant of farming, inflicted with poverty, far away from the managers, a calamity that goes unnoticed by city-dwellers. All these facts combine to make Chagas’ Disease a silent tragedy that not only sever lives but distort them, making them unproductive and vulnerable long time before the death occurs.

Currently there are no effective treatments against Chagas’ Disease. The compounds already used, Nifurtimox and Benznidazole have plenty of side effects, besides they are only effective at the early stages of the infection, which are often unnoticed, in later stages, they are totally ineffective. Hopefully, new therapeutic alternatives are being designed, tailor made to attack the parasite without interfering with the host metabolism. Among the new approaches to deal with Trypanosoma cruzi are targeting the systems that allow the parasite’s consumption of glucose, its sole source of energy in the bloodstream and its systems for sterol synthesis, both necessary for the survival of the parasite. Several compounds that target the enzymes responsible for these systems have been successfully assayed, showing in vitro and in vivo activity against the parasite, besides having low or no detectable toxicity in cultured macaque cells and mice.

However, drug development is still a expensive endeavor and we might have to wait for long time before a cure is achieved.


More info about Chagas' Disease:


Doctors without borders
Wikipedia

And a rough translation of a fragment of "Chagas, a silent tragedy", by Eduardo Galeano:

It doesn't explode like bombs, it doesn't sound like shots. Like hunger, kills silencing. Like hunger, kills the silent ones: to the ones who live condemned to the silence and die condemned to oblivion. Tragedy that doesn't sound, sick people that do not pay, a disease that doesn't make any sell. Chagas' disease is no business that attracts pharmaceutic industry nor subject interesting to politicians or journalists.

About my thesis. Soon, first results

I have decided to make public the preliminary models and kinetic results from my thesis. I will post some code here, but most likely I will upload the files (Fortran files and Mathematica notebooks, unfortunately I am not going to be able to do it 100% on FLOSS) somewhere. The title of the thesis is: "Control y regulación de la Glicólisis en Trypanosoma cruzi: Un enfoque teórico-práctico", which translated would be something like "Control and regulation of Trypanosoma cruzi's Glycolysis: A theoretical-practical approach". I will make a model of T. cruzi's Glycolisis based on Ordinary Differential Equations and an Metabolic Control Analysis of the model, trying to find which enzymes and/or transporters comprise the majority of the control of the glycolytic flux of the pathway. According to Solomon Nwaka and Alan Hudson, in their paper Innovative lead discovery strategies for tropical diseases, published in Nature RFeviews, Drug Discovery, November 2006 finding proper targets is important because:

Many compounds active in protein-based assays are inactive in whole cells.
This can be due to failure to enter intact cells but can
also occur because the chosen molecular targets are not
in fact essential to the microbes. The latter issue sug-
gests that more work on target validation is needed to
increase confidence levels in the selection of protein
candidates for Hight-Throughput Screening campaigns. The initial challenge of
identifying molecular targets that are crucial to parasite
survival, coupled with the identification of whole-cell
active compounds, is formidable (...)

My favorite analogy to explain to my family what the hell I am doing is to ask them if they have a gun, few bullets and a car is coming to them at 100 kph, will they aim to the rear-view mirrors? I tell them I try to find the vital parts of the parasite that can be targeted in a safe way, without risk to us in order to not waste bullets against non relevant targets, since resources for research are scarce here. We have chosen to model T. cruzi's glycolysis because this pathway is very particular in trypanosomatids, it is physically located inside an special organelle called the glycosome. the enzymes are regulated in a non traditional
fashion, do not share a lot of similarity with mammalian enzymes and glycolysis is essential for the survival of the parasite. Besides this, there is a whole research line on these kind of models for other trypanosomatids, but not in T. cruzi. I have spotted some mistakes on the kinetic equations of some of the models I am basing my work on and therefore, improved models of other kinetoplastids could be developed too, if there is enough time. And I think that besides replicating the work for T. cruzi, it is also possible to develop some original research concerning these models. Stay in touch.

PS: Around the weekend I should post/upload a corrected version (minor details of transcription and nomenclature) of Daniel Guerra's model of Trypanosoma brucei's glycolysis in his doctoral thesis from 2005, Glucose Metabolism of Trypanosoma brucei and Leishmania mexicana.