Malaria presents a formidable global challenge. It affects more than 200 million people worldwide every year, and more than 1 million people die from it, primarily pregnant women and children under the age of 5 years. Resistance to existing anti-malarial medications is a constant, and vaccines have not proven effective. But the disease also presents a unique opportunity for researchers to uncover innovative solutions. As a result, even the cash-conscious National Institutes of Health (NIH) is investing in malaria research.
Boston Children’s Hospital physician Jeffrey Dvorin, MD, PhD, recently received a High-Risk, High-Reward New Innovator Award from the NIH. The award is reserved for early-stage investigators whose research has potential for significant impact, but who may lack enough data for a traditional NIH R01 grant. Dvorin will use the $1.5 million, five-year grant to pursue research that could lead to new tools to combat malaria.
The challenges of treating malaria begin at the molecular level. To develop new anti-malarial tools, the research community needs to understand how the parasite replicates. Determining which genes are essential to parasite replication could provide the data needed to develop new medications or an effective vaccine. But scientists have not yet determined functions for more than half of the 5,500 genes in Plasmodium falciparum, which causes the majority of malaria infections in Africa.
Innovation and successful NIH funding applications have much in common. Both are methodical, step-by-step processes that depend on role models and persistence.
As a young researcher pondering the genetic challenges of malaria, Dvorin cultivated relationships with established clinicians and researchers, who urged him to think big. Michael Wessels, MD, chief of Infectious Diseases at Boston Children’s, encouraged him to consider innovative techniques and gave him the freedom to pursue outside collaborations. At the Harvard School of Public Health (HSPH), Manoj Duraisingh, PhD, helped to shape his view of malaria genetics, and Dyann Wirth, PhD, provided more senior career mentorship, such as identifying opportunities in malaria research.
With encouragement from his mentors, Dvorin applied for various grants to test his approach to the genetics of P. falciparum. A pilot grant in 2012 from the William F. Milton Fund at Harvard University served as the initial seed for Dvorin’s current NIH win. This award, offered Harvard-wide, provides funds to help researchers generate the preliminary data needed to convince the NIH or other funding sources to further support their research. Dvorin used the $40,000 grant to complete preliminary experiments to determine if his approach, applying a technique known as forward genetics, was feasible.
Dvorin used a second grant, a two-year, $47,000 award from the Boston Children’s Hospital’s/Massachusetts Institute of Technology’s collaborative fellowship program, to recruit an additional post-doctoral researcher to his laboratory to perform the pilot proof-of-principle studies (unpublished) for the project.
“Institutional support for early stage investigators has been critical for the exciting research taking place in my lab now,” Dvorin says. “As my research moves forward, I hope that the hard work of the postdoctoral fellows in my lab, together with some luck, will allow us make a significant impact on a globally important disease.”
The NIH New Innovator Award grant adds critical support for the research.
To date, the process of pinpointing essential genes has hinged on a slow, one-gene-at-a time process known as reverse genetics. The approach applies classic genetic techniques to mutate specific parasite genes individually to determine the function of each gene and its effect on phenotype. Using this method, it takes researchers three to four months (or longer) to evaluate individual genes.
Dvorin aims to accelerate the process by approaching it from a different direction, devising a forward-genetic system for P. falciparum. Successfully used in the past in yeast and other organisms, forward genetics starts with a target phenotype, such as growth or a behavior, and seeks to identify the genes responsible for it—often by using agents to induce mutations. Researchers can then breed successive generations of the mutant organisms and examine their phenotype.
Dvorin plans to apply this method to malaria for the first time. He’s adapting forward genetics, inserting a mutagen in a dormant state into the parasites and then turning it on. Selecting parasites with the dormant mutagen prior to activation could increase the yield of parasites available to study by more than 10,000-fold, Dvorin believes.
Next, he will seek to identify mutations and then follow this pool of parasites through several generations to determine which mutations disappear in successive generations. Those mutations, which may have affected an essential gene (thereby causing the parasites to perish), may point to essential genes that could provide potential targets for new anti-malarial drugs.