Whole organism biology and life histories

There is still much to learn about our basic concepts, life history stages, and even life cycles of medically important parasites. Much of our knowledge in this area was generated in the early part of the 20th century but was never revisited using modern approaches. For example, the life cycle of Strongyloides stercoralis was established by Friedrich Fuelleborn during the 1910s and later in the 1920s by Masao Nishigoii, who found evidence for autoinfection, but then was not systematically reinvestigated for 70 years until Gerhard Schad and Linda Mansfield used modern radiotracing methods to reveal multiple alternative pathways by which infective larvae migrate through body tissues to become adult worms [7, 8]. Similarly, R. A. Wilson and his colleagues have identified novel mammalian tissue migration pathways for schistosomes [9]. It’s conceivable that similar findings could be made for many other human parasites. Today, graduate and postdoctoral training is heavily focused on molecular and cellular studies, but often at the expense of whole organism biology. It is true that for neglected disease pathogens, the field of molecular parasitology that took off beginning in the 1980s has yielded important and fundamental insights as well as innovative approaches to drugs, diagnostics, and vaccine development [10]. But our collective expertise in the biology of whole organisms may be disappearing with recent retirements, and, so far, there have been minimal efforts to develop restorative training programs in this area.

Model organisms and single-cell combinatorial indexing RNA sequencing

Many of our greatest scientific discoveries in molecular biology were achieved using model organisms such as Caenorhabditis elegans and Drosophila melanogaster. We have started to make progress in tapping into the rich diversity of technologies developed for such model systems and applying them towards neglected pathogens [11–13], but this approach is still underutilized. In a new development, the genomics group at the University of Washington published a single-cell combinatorial indexing RNA sequencing (sci-RNA-seq) approach to allow for a molecular cell-by-cell profile of C. elegans [14]. Similar approaches could identify rare cell types in parasitic helminths or cell types unique to parasites, which could serve as the basis for new therapeutic approaches.

Functional and comparative OMICs and gene editing

In related studies, a central repository of genes from C. elegans and other free-living and parasitic nematodes has been curated into a WormBase for comparative genomics [15, 16], while new functional tools such as RNAi, transgenesis, and CRISPR/Cas genome disruption and editing are revealing new information about human parasites, including new targets for intervention [17, 18]. Genome editing has also been proposed as an approach toward producing attenuated parasites for functional studies or for vaccine development [19].

Ecology and evolution and mathematical biology

Many of our modern approaches to global deworming for soil-transmitted helminth infections and schistosomiasis are based on the modeling and population dynamics studies of Anderson and May conducted during the 1980s [20]. Mathematical biology has potential importance for all of our major neglected disease control approaches. In turn, parasites have evolved with their intermediate and definitive hosts to establish amazingly complex and intimate associations [21]. The sciences of ecology and evolution have critically important roles in promoting our understanding of the host–parasite relationship [21].

Systems biology and immunology

Systems biology has provided a new framework for understanding complicated host–parasite interactions for malaria and other systems [22–24], while the relatively new field of systems vaccinology could transform how we select vaccine candidates and advance them through clinical development in an accelerated sequence [25]. The potential value of systems vaccinology was dramatically illustrated by a recent modification in immunizing human volunteers with the RTS,S malaria vaccine [26]. While previous immunization protocols elicited significant levels of host antibody responses, the overall level of protection was considered modest. However, through fractional dosing and alterations in immunization schedule, a significantly improved level of immunity was obtained [26]. Ideally, through systems vaccinology, such findings could have been obtained earlier in the vaccine development process. In this regard, a new Human Vaccine Project to better understand the human immune system and how it responds to vaccines has been launched [27].

The areas of basic science discussed here are by no means comprehensive but instead were selected to illustrate the enormous number of exciting findings that might lie ahead. During the 1980s, as an MD–PhD graduate student, I was privileged to work in one of the first laboratories devoted to applying the new science of molecular biology to the study of animal parasites [10]. My scientific career began as a basic scientist isolating new proteins and genes from hookworms to understand how these parasites invade human tissues. Only later did I look at how we might interfere with these molecular processes as an effort to develop new vaccines. Over time, my career transitioned from basic to translational science, ultimately folding in a program of public engagement through policy and advocacy.

Today, we are once again at a new threshold when active pursuit in the basic science areas highlighted above will provide an exciting tranche of insights for tropical disease pathogens and host–pathogen interactions. We could soon gain mission-critical information about molecular and cellular biology and how it integrates within biological systems and disease ecology. If adequately supported, these findings could jump-start a new generation of translational medicine and control tools. In so doing, we will help to ensure that a robust pipeline of neglected diseases interventions can continue. Just as the world’s poor deserve access to food, water, shelter, and essential medicines, they also deserve access to innovation [28]. We can do better to promote basic research to benefit marginalized and impoverished populations.