New Tools and Models for Improving Impaired Gut Function in the Developing World

In our Grand Challenges Explorations Round 12 call for proposals, we asked the global community for ideas about tools and models to enable us to better develop new therapies for acute secretory diarrhea (ASD) and environmental enteric dysfunction (EED). The community responded, and we received over 100 ideas from 24 different countries. These ideas ran the gamut from pig models to gut-on-a-chip to tissue-engineered organoids. All proposals received went through the blinded, champion-based review process for GCE, where reviewers focused on the idea presented in the two pages. Ideas included both in vivo and in vitro models to recapitulate the gut dysfunction seen in children suffering from ASD and/or EED, and tools to help us better understand and characterize these conditions. We're very excited about the ideas we received, and we're looking forward to expanding that list of great ideas in our GCE Round 13 call for proposals.

These and all the projects funded under the GCE Round 12 topics will be available at grandchallenges.org in mid-May 2014. Please check back then to read more about them. In the meantime, we encourage you to read the topic, the background we provided in our Fall 2013 blog, below, and send us your great ideas for this round.

In the call, we clearly define examples of what we will consider for funding and what we will not consider for funding. We encourage you to read the topic carefully; proposals that do not address the challenge laid out in the call are screened out early in the process and will not be funded.

As a reminder, we are not looking for new drugs or interventions in this call, we're looking for new tools and models that, once more fully developed, will enable the development of new interventions for ASD and EED.

*******************

September 26, 2013

RICHARD ELLIOT & THOMAS BREWER

Many children in the developing world suffer and die from two major conditions: acute secretory diarrhea (ASD) and environmental enteric dysfunction (EED). Acute secretory diarrhea causes nearly 800,000 child deaths each year, most of these in poor, underserved populations. In addition, many of these children suffer from a complex syndrome called Environmental Enteric Dysfunction (EED)- broadly characterized by growth stunting and cognitive impairment due to gut dysfunction. The impact of EED on mortality and morbidity, though hard to quantify, is believed to be enormous. Given the impact of these diseases on children in the developing world the Foundation is committed to develop new interventions for ASD and EED.

Acute secretory diarrhea: Children needlessly die from ASD, as oral rehydration solution (ORS) - a simple sugar and salt solution- can be mixed up at home and given to the child to restore water and electrolytes, thus preventing death due to dehydration. So why are children still dying? The unfortunate answer is that ORS, or ORS supplemented with zinc, doesn't appear to work- i.e. it does not offer symptomatic relief for the patient. Children given ORS continue to experience diarrhea, or may even have increased stool output due to better hydration, and thus although the solution is working to restore electrolytes and treat fluid loss- keeping the child alive- parents and caregivers stop giving the child ORS. To combat this problem, we are interested in developing anti-secretory agents which acts on the host (versus the pathogen, which might lead to development of resistance) and could be used in conjunction with ORS to decreased water loss, thus encouraging caregivers to continue to use ORS and improve outcomes.

Environmental enteric dysfunction: Unlike for ASD, we do not yet have an effective treatment for EED. However, we believe that if we can discover and develop interventions to improve the many key functions of the gut, including nutrient absorption, protective barrier, niche for healthy microbiome, and a protective mucosal immune response, we will be able to help prevent and treat EED. We believe improved gut function would lead to better outcomes for children with EED, including improved nutrition, improved immune response to vaccines, decrease susceptibility to pathogen infections, decreased stunting and cognitive impairment, and generally a higher quality of life.

Developing new interventions for ASD and EED: However, we require better scientific tools, models, and assays to efficiently develop new therapies for ASD and EED. Thus, our goal with this initiative is to develop a toolbox of translational models and assays to support the research and development of new therapies for gut dysfunction- such that, someday in the future, it will be a rare event indeed when a child dies from diarrhea or a dysfunctional gut.

For this Grand Challenges Explorations (GCE) round, our challenge to you is to send us your great ideas for new tools and models that will enable the discovery and development of new interventions to improve gut function. For example, we're interested in your ideas to help us develop and validate new models – things we can try on a benchtop in a laboratory setting using innovative approaches – and other tools to facilitate the development and testing of new therapies for ASD and EED. Please note that we are not looking for new therapies, or proposals involving clinical trials in human volunteers or patients, in this round of GCE. The first hurdle is understanding how we would even test and compare new therapies; hence our call for new enabling tools and models that will support the development of new tools and models down the road.

We look forward to your great ideas. We especially encourage researches who may work predominately in research areas outside of human diarrhea and infectious gut dysfunction, such as veterinary medicine, cancer biology, or researchers focused on other gut conditions such as irritable bowel disease or Celiac disease (for example), who may bring in new perspectives and leverage ideas and learnings from other areas.

With your help, we can move one step closer to saving those 800,000 lives a year and give children suffering from ASD or EED a chance for a better life. What a grand goal for this round of Grand Challenges Explorations!