Gates Foundation's $100k grant supports global health research

A $100,000 Grand Challenges Explorations grant from the Bill & Melinda Gates Foundation will support a global health research project conducted by polymer scientist Gregory Tew to pursue ideas that have never before been tested in fighting infectious diseases such as pneumonia, tuberculosis and diarrhea.

The project is one of 81 grants by the Gates Foundation in the second funding round of Grand Challenges Explorations, an initiative to help scientists around the world explore bold and largely unproven ways to improve health in developing countries. The grants were provided to scientists in 17 countries on six continents. To receive funding, Tew showed how his idea falls outside current scientific paradigms and might lead to significant advances in global health. The Grand Challenge is highly competitive and received more than 3,000 proposals in this round.

Tew and colleagues had developed synthetic molecules they call antimicrobial oligomers (AMO) that behave like a class of natural immune-boosting molecules known as host defense peptides (HDPs). The researchers chose to mimic HDPs for several reasons, including that they “display very broad spectrum action against bacteria, yeast, fungus, and even viruses.” Also, unlike most conventional antibiotics, their unusual structures mean HDPs mostly target the cell membrane, where they have a relatively low propensity to develop resistance—a quality increasingly valued as more and more drugs gain antibiotic resistance.

Now, taking the inventive next step supported by the grant, the researchers plan to explore which of several possible parts the new synthetic AMOs play in modulating the mammalian immune system. Tew and Juan Anguita, assistant professor of Veterinary and Animal Sciences, will conduct experiments to test whether the synthetic AMOs reliably activate host immune responses. “Although we have shown that these AMOs already mimic the antibacterial activity of HDPs,” Tew says, “the larger question remains whether they can signal the immune system as effectively as the natural peptides do.”

One of the HDPs’ most important roles is acting like a platoon leader, rallying the host’s specialized immune defense calls to fight disease at the infection site. This leads the host immune system to identify invaders and produce specialist cytokines, for example, to fight them. HDPs also use mechanisms such as producing phagocytes to surround and destroy foreign material, or reactive oxygen species (ROS) and nitrogen radicals, to attack infection in other ways. Crucially, HDPs work without stimulating harmful inflammation.

“We propose to explore how synthetic AMOs interact with the immune system and test a new immuno-modulating therapy, specifically on bacterial pneumonia strains that in humans account for a significant number of deaths worldwide,” Tew says. “If we’re successful, it would imply that we might have further success in using AMOs against viruses, even including HIV.”

Medical interest in AMPs is not new, the researchers acknowledge, but it has run into some challenges they hope to address. For example, despite extensive efforts by drug and biotechnology companies, no one has yet found a way to administer AMPs intravenously to treat infections. The scientists hope a synthetic, non-toxic alternative can address this, plus material costs, toxicity, limited efficacy and limited tissue distribution, they explain.

Preliminary data suggest that synthetic AMOs are intrinsically bactericidal and act directly on microorganisms, but they may also be able to command the immune cell’s defense weapons to fight infection. In a series of cell-level experiments, Tew and Anguita expect to be able to detect direct killing of bacteria by AMOs and to identify specific cells affected by them. They’ll also watch for the platoon-leader adaptive defense effect, marked by production of antibacterial compounds such as ROS and various cytokines.

Anguita and Tew will complement their cell work with experiments in strains of transgenic mice that retain their innate immune responses, but whose macrophages and dendritic cells are unable to produce antibacterial compounds such as ROS. “If our results warrant it, we’ll determine the signaling pathways affected by AMOs and identify whether the potential effect is mediated by the interaction of AMO with a specific cell surface receptor” Anguita says.

By combining the cell-level and whole-animal experiments, Tew and Anguita expect to see whether AMOs can initiate key immune responses that rid cells of the pneumonia-causing bacteria. Thus, Tew notes, “these experiments will allow us to conclusively rule in or rule out particular contributions from the immune system.”

“The winners of these grants are doing truly exciting and innovative work,” according to Tachi Yamada, president of the Gates Foundation’s Global Health Program. “I’m optimistic that some of these exploratory projects will lead to life-saving breakthroughs for people in the world’s poorest countries.”

Grand Challenges Explorations is a five-year, $100 million initiative of the Gates Foundation to promote innovation in global health using a streamlined grant process. Applications are limited to two pages, and preliminary data are not required. Proposals are reviewed and selected by a committee of foundation staff and external experts, and grant decisions are made within approximately three months of the close of the funding round.

More Information

Gates Foundation Grand Challenges

May 14, 2009.