The Bill and Melinda Gates Foundation announced today a second round of its global health Grand Challenges Explorations program. With mainstream science stymied on key disease fronts, the Explorations program sought radical new approaches from non-traditional sources. In relaxing the parameters of expertise, size of lab, and geography, the foundation in the first round attracted an outpouring of more than 4,000 grant applications from more than 100 countries. Announcement of the round one winners, originally scheduled for Sept. 1, has been pushed back to October.
The foundation is unsated. The round two topics essentially repeat all the previous topics but with greater specificity and some broadening. The Explorations program now also seeks novel approaches to pneumonia, diarrhea, and malaria, joining HIV and TB, which have been held over from round one. Also back is the search for overcoming drug resistance, a serious problem not only in tuberculosis in but "superbugs" like Methicillin-resistant Staphylococcus aureus (MRSA). The sole new addition is a call for new tools for eradicating malaria.
With so many AIDS and TB proposals presumably in hand, the request for more suggests the difficulty of descrying a winner on the basis of a two-page application and the foundation's preference for backing many horses. Leaders of the AIDS vaccine research effort dramatically lowered expectations last week in the aftermath of the latest failed vaccine trial. "We may not be able to develop an HIV vaccine that is highly effective in the classic sense of successful viral vaccines," wrote Anthony Fauci and Margaret Johnston in the New England Journal of Medicine. Fauci is director of the National Institute of Allergy and Infectious Diseases. He also serves on the scientific board for the Gates Foundation Grand Challenges.
An AIDS vaccine faces "enormous scientific challenges," according to Fauci and Johnston. Successful vaccines deftly trigger a natural, effective immune response. But the natural immune response against HIV is "completely inadequate." There's nothing there to trigger. Further, HIV quickly ensconces itself within human DNA, after which neither the immune system nor even extended, highly active antiretroviral therapy can eradicate the virus. Thus, among the options countenanced in the round one Explorations for beating HIV was "an artificial adjunct to the immune system" to overcome the limits of natural immunity.
Antibiotics have given humans an astonishing dominance over familiar and long-time foes, bacteria. However, as the dawn of the 21st century approached, scientists openly worried about the antibiotic era becoming "a footnote in human history." The golden age of antibiotic discovery largely ended in the late 1960s. A dry spell of 40 years ensued in which no new chemical class of antibiotics was successfully introduced into the clinic. Resistance now develops faster than before when new antibiotics, derived from earlier classes, begin to be used.
Researchers had hoped the genomics revolution might also revitalize development of antibacterials. However, the DNA sequences of bacteria have yet to betray any broad avenues of attack. Should new classes of drugs emerge, they could be the last since genomics puts on display the entire plan of the organism. Thus, the importance of defeating resistance. In the language of the Explorations, "We need new ways to create drugs that are less likely to be made ineffective by pathogen [bacterial] evolution ..."
Malaria and the mosquitoes that carry it demonstrate a seemingly effortless yet deadly capacity for developing resistance. Chloroquine therapy has ceased to be effective in large and growing swathes of malaria-afflicted regions; mosquitoes around the world are increasingly shrugging off the ill effects of DDT, a key component in eradicating malaria from the U.S. [PDF] in the 1940s.
The Grand Challenges Explorations supplement anti-malaria efforts already in progress under the auspices of the initial Grand Challenges, launched in 2005. Researchers from that earlier initiative are working to develop genetic methods to "deplete or incapacitate a disease-transmitting insect population." Strategies being investigated are very high tech and, if not high risk, distinctly high fright. Just genetically engineering even large numbers of mosquitoes to pass on traits such as sterility, inability to fly, or premature death is unlikely to work in taking over entire mosquito populations. Instead, scientists at Imperial College in London are working to change the mechanism by which mosquitoes manage their own DNA in a way that "drives" genes into the population at a much faster rate than natural genetic recombination. Advocates point to the "reversibility" of this process in the event something goes awry.
A second Grand Challenge effort focuses on a chemical strategy for tackling mosquito-borne illness. Bed nets, impregnated with insecticide, are a key defense against mosquitoes, but the chemicals are not good for humans. Researchers at Virginia Polytechnic Institute and State University aim to produce an insecticide that assembles inside the central nervous system of the mosquito from components that in themselves are non-toxic. Researchers at Columbia and Vanderbilt have devised a kind of mosquito nose in a petri dish, enabling the large-scale testing of different compounds for wreaking havoc with the mosquito's sense of smell. The team itself exudes prestige, being comprised of two Howard Hughes medical researchers, Lawrence Zweibel and Richard Axel. Axel is a Nobel laureate.
Few of the 4,000 Explorations applications seeking $100,000 grants are likely to present such distinguished pedigrees. But one might offer a seemingly absurd idea which might turn out to be right, if it is somehow chosen for a grant. The announcement next month of the round one winners will reveal something of the quality and character of the vast applicant pool and the criteria by which the foundation plucked out its selections. A much longer suspense of years will have to elapse before the foundation's judgments and conjectures are validated or refuted.