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"Malaria currently kills nearly two million people each year, mostly children in countries around the world, and has become resistant to some drugs."

Malaria is one of the oldest documented human diseases recorded in history. Far from over, it currently kills nearly two million people each year, mostly children in countries around the world.

As early as the 1600s, quinine from the bark of cinchona trees was found to cure malaria, and in the 1940s, a synthetic form called chloroquine was developed. So why are there still so many deaths due to malaria?

Dr. Paul Roepe, Professor of chemistry, at Georgetown College, Professor of biochemistry, cellular and molecular biology at Georgetown University Medical Center, and co – Director of the University’s new Center for Infectious Disease, wants to find out why and help stop malaria in its tracks.

Increasing evidence points to how malaria continues to evolve and “outsmart” the drugs that used to be effective in controlling its spread. While the worldwide incidence of malaria has stayed fairly constant, the number of deaths each year is increasing for several reasons. Some of the world’s population that contracts malaria also has AIDS or other diseases, and / or is malnourished, possibly increasing the severity of malaria symptoms. Another troubling reason is that in recent years malaria parasites have grown resistant to the modern drug regimens.

Roepe focuses his research on understanding the basis of this resistance. His laboratory examines the molecular details of drug resistance in the parasite, transmitted from mosquitoes to humans, that causes malaria. The parasite, Plasmodium falciparum, is tiny—so small that it resides in individual red blood cells (RBC) themselves. Not only does the parasite take up residence in a RBC that is smaller than 8 microns, the parasite grows at an alarming rate inside the RBC: almost 1000 fold in a little more than two day’s time. (See animations of the Plasmodium falciparum life cycle).

By understanding the mechanisms that permit Plasmodium to resist the effects of drugs meant to destroy it, Roepe and colleagues can then help develop new drugs that overcome the resistance. The complexity of these questions requires technical skills and creative approaches which Roepe brings together in collaborations that cross many disciplines.

Trained as a physical chemist, Roepe has a long history of crossing disciplinary boundaries. These collaborations have resulted in significant findings. Five years ago, Roepe established a collaboration with Dr. Jeff Urbach, Professor and chair of the Georgetown Department of Physics. Together, they developed new ways to image living malarial parasites inside RBC. In recent years, Roepe and Urbach have applied these methods to measure changes in parasite intracellular pH and other features that are related to drug resistance. In particular, their team has focused considerable effort at trying to understand the parasite’s digestive vacuole, which is where chloroquine and other drugs work.

Roepe and Urbach hypothesized that there would be a difference in the size of the vacuole for drug sensitive vs. resistant parasites. However, they needed to think small—measuring volume changes for an organelle, inside the parasite, inside a red blood cell can’t be done through ordinary means! Earlier, Roepe’s group found that the drug resistant Plasmodium digestive vacuole is more acidic (pH=5.2) than the drug sensitive Plasmodium digestive vacuole (pH =5.6). With the new imaging tools developed in collaboration with the Urbach group, the implications of this acidification were analyzed in more depth. Among other results, the team found that this acidification correlates with larger vacuole size. These simple results have important implications for new drug design.

In the past year or two, the collaboration with the Urbach lab has led to even faster and more sensitive ways to make these measurements. Special imaging techniques allow the researchers to quantify changes in not just pH and volume, but a variety of other characteristics that distinguish drug resistant malaria from drug sensitive.

In another key collaboration, the Roepe group uses such molecular – level information about drug resistant malaria to synthesize new drugs with the laboratories of Drs. Christian Wolf and Angel de Dios (both Associate Professors of Chemistry). The synthetic chemistry expertise of the Wolf laboratory, the structural information provided by high field NMR spectroscopy used in the de Dios laboratory, and the biochemical information from the Roepe group, when combined together, form a truly unique environment for antimalarial drug discovery. Roepe and many others believe that such multi – laboratory “team oriented approaches” are the best hope for tackling major interdisciplinary challenges in science, such as the current global tragedy of antimalarial drug resistance.

Roepe explains that all fields of science can contribute to malaria research. He has a special skill in building networks among Georgetown scientists in both a number of College departments and at the Medical Center. Undoubtedly this skill is one of the key ingredients in his ability to attract funding: Roepe is the sole principal investigator (PI) on two major NIH grants and the co-PI on two more, which together, have brought more than six million dollars in research funding to Georgetown. One of these grants, in the amount of $1.94 million dollars, funds the collaborative work between the Roepe, de Dios and Wolf laboratories described above. All three are members of Georgetown’s Center for Infectious Disease, as well as Chemistry dept. faculty members.

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