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Grand Challenges is a family of initiatives fostering innovation to solve key global health and development problems. Each initiative is an experiment in the use of challenges to focus innovation on making an impact. Individual challenges address some of the same problems, but from differing perspectives.

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Rapid Cryptosporidium Drug Target Identification

Gregory GoldgofUniversity of California, San DiegoLa Jolla, California, United States
Grand Challenges Explorations
Cryptosporidium Infection
14 Jun 2017

Gregory Goldgof and Elizabeth Winzler of the University of California, San Diego in the U.S. will use a genetically modified drug-sensitive yeast strain to quickly and inexpensively identify the cellular target of compounds that can kill the parasite Cryptosporidium, which is a major cause of diarrhea-associated deaths of young children in developing countries. Currently, there is only one treatment available and it is of limited use in some of the more severe cases. The yeast strain has been modified to lack transporter proteins that remove toxic compounds from the yeast cells. By treating the modified yeast with a selection of compounds that can kill Cryptosporidium, they hope to drive some of the yeast cells to develop resistance by mutating genes that are responsible for the drugs activity. By sequencing the resistant yeast using whole genome sequencing, they can then discover the likely target of the drug and how it kills the parasite. This would help to develop new drugs that may be more effective.

Novel Therapy Targeting the Cryptosporidium Virus

Nigel YarlettPace UniversityNew York, New York, United States
Grand Challenges Explorations
Cryptosporidium Infection
14 Jun 2017

Nigel Yarlett of Pace University in the U.S. will determine whether a virus that infects the intestinal parasite Cryptosporidium is a valuable target for developing drugs against the associated chronic diarrheal disease, which causes substantial morbidity and mortality in young children in low-resource settings. The double-stranded RNA Cryspoviruses are not harmful to the parasite, and instead likely enhance the parasite’s ability to infect and harm humans. They will create a continuous in vitro culture of the Cryptosporidium parasite carrying viruses that will be genetically modified to fluoresce for easy monitoring, and also use RNA interference to generate a parasite strain that does not contain any viruses. These tools will be used to study the role of the virus in the growth and development of the parasite. Ultimately, a drug targeting the virus, rather than the parasite itself, may be less toxic to the good bacteria in the human gut, and less likely to drive the development of drug resistance.

The Spiny Mouse for Screening Contraceptives

Hayley DickinsonMonash UniversityClayton, Victoria, Australia
Grand Challenges Explorations
Contraceptive Discovery
14 Jun 2017

Hayley Dickinson of Monash University in Australia will evaluate the spiny mouse, which is the only rodent that naturally menstruates, as a new animal model for developing and testing contraceptives. Menstruation is an essential feature of human reproduction, and is regulated by hormonal contraceptives. However, current contraceptives like the contraceptive pill can cause side effects such as anxiety and low libido. A small animal model that mimics human menstruation would be valuable for testing new contraceptives that have fewer side effects. The menstrual cycle of the spiny mouse, like that in humans, involves progesterone production from a transient endocrine gland. These mice also display cycles of anxiety behavior similar to premenstrual tension. They will validate it as a model for contraceptive drug discovery by analyzing the effects of current human contraceptives on fertility, hormonal profiles, vaginal cytology, and behavior.

Dynamic Census Project for Malaria Elimination in Mozambique

Ayumi AraiCenter for Spatial Information ScienceKashiwa-shi, Japan
Grand Challenges Explorations
Malaria Analytics
14 Jun 2017

Ayumi Arai of the University of Tokyo in Japan will use anonymized mobile phone data to produce a dynamic census that reveals the movements of all individuals in a population over time broken down into age and gender to help reduce regional malaria transmission. Human mobility and distribution play key roles in malaria transmission but it is difficult to monitor the movements of everybody in a population. They will gather call detail records and use them to develop an algorithm that considers non-phone users such as children and the elderly, and can predict gender and age group, which are linked to malaria vulnerability. To generate the dynamic census they will build a system incorporating application programming interfaces to support different input and output data formats to promote use by third parties and in other countries. They will apply the system to create a dynamic census of Mozambique, and validate it using data from transport networks and small-scale surveys.

High-Throughput Screening for Novel Contraceptive Agents

Francisco DiazPennsylvania State UniversityUniversity Park, Pennsylvania, United States
Grand Challenges Explorations
Contraceptive Discovery
14 Jun 2017

Francisco Diaz of Pennsylvania State University in the U.S. will develop a high-throughput screening method to identify compounds that can block two biological events essential for female fertility without affecting ovulation or hormone production in order to identify new contraceptives with fewer side effects. These two events, which occur at the same time, are cumulus expansion, whereby cumulus cells release from the oocyte to enable it to enter the oviduct, and oocyte maturation, whereby the oocyte divides to produce the egg and a smaller polar body. They will extract cumulus oocyte complexes from primed female mice and apply them to a microwell array prototype that will contain 1,024 wells coated with different test compounds and connected in groups by microfluidic channels. Oocytes in the wells will be stimulated to undergo first cumulus expansion, and, after removal of cumulus cells, oocyte maturation. The ability of each compound to inhibit each step will be assessed by automated inverted microscopy. They will first optimize their platform using known inhibitors and then test it using a library of 1,200 FDA approved molecules.

Documenting Male Future Contraceptive Preferences in Nigeria

Francis EremuthaWomen Friendly InitiativeAbuja, Nigeria
Grand Challenges Explorations
Family Planning
14 Jun 2017

Francis Eremutha of the Women Friendly Initiative in Nigeria will develop and conduct surveys to identify the reasons why Nigerian men prefer certain contraceptives to help design new ones that men are more likely to use. Currently, there are limited male contraceptive options available, and they suffer from being ineffective, undesirable, or irreversible. The surveys will be both field-based and online, and will be designed to capture the opinions of married and unmarried Nigerian men between the ages of 15 and 60 across six states. They will develop the research protocol in collaboration with the Federal and State Ministries of Health, and train field workers, develop collection tools, and perform quantitative and qualitative analyses of the data.

A Platform for Identifying Drugs Targeting Germ Cells

Randall PetersonUniversity of UtahSalt Lake City, Utah, United States
Grand Challenges Explorations
Contraceptive Discovery
14 Jun 2017

Randall Peterson of the University of Utah in the U.S. will develop a zebrafish model for high-throughput screens to identify compounds that inhibit the formation of gametes, i.e., sperm or eggs, (gametogenesis), which could lead to male and female contraceptives that last for weeks or months after only a single dose. They will generate transgenic zebrafish lines that express a selection of four fluorescently-labeled markers for different stages of gametogenesis that can be rapidly quantified to measure the effects of candidate compounds on blocking gamete production. The suitability of these zebrafish lines for high-throughput multi-well compound screens will be tested using known inhibitors of gametogenesis.

Spermatogonia-Meiosis Transition as a Contraceptive Target

Paula CohenCornell UniversityIthaca, New York, United States
Grand Challenges Explorations
Contraceptive Discovery
14 Jun 2017

Paula Cohen of Cornell University in the U.S. will develop a spermatogonial stem cell culture system to investigate whether the first stage of sperm formation – meiotic division of the spermatogonial cell – is a valuable target for the development of effective male contraceptives. Targeting this early stage rather than later stages has several advantages including that it is accessible to compounds in the circulation, and that the effect on fertility would be rapid and reversible. However, little is known about the molecular mechanisms regulating meiotic entry. They will develop a spermatogonial stem cell culture system carrying fluorescent reporter proteins that signal cell state and meiotic entry. They will then use CRISPR/Cas9 genome editing to mutate genes known to be involved in meiotic entry and stem cell maintenance to test the system, and use CRISPR interference to test the effect of switching one of those gene off and then back on again on the spermatogonial stem cells. Once the system has been set up, it can be used to screen for new genes involved in meiotic entry that would be good candidates for the development of novel male contraceptives.

Implicit Measures of Women's Beliefs About Contraception

Maria GalloOhio State UniversityColumbus, Ohio, United States
Grand Challenges Explorations
Family Planning
14 Jun 2017

Maria Gallo of Ohio State University in the U.S. will adapt a validated computer-based psychological test known as the Implicit Association Test to measure the true opinions of women in Vietnam on hormonal contraceptives in order to encourage use. Vietnam has one of the highest rates of abortion worldwide. Although hormonal contraceptives are available, it is thought that many women are worried about using them and instead use alternative methods that are generally less effective. Finding out exactly what these women think about hormonal contraceptives in order to dispel any myths is challenging because many people either don’t say or don’t realize what they think for a variety of social and psychological reasons. The Implicit Association Test overcomes this challenge by measuring the strength of the associations an individual makes between two pairs of contrasting concepts based on speed. They will adapt the test to determine opinions about the intrauterine device and oral contraception by measuring the strength of their associations with good or bad, and natural or unnatural. This will be tested using a cross-sectional study of 500 non-pregnant females.

Conditional Protein Degradation Tool for Cryptosporidium

Sumiti VinayakUniversity of GeorgiaAthens, Georgia, United States
Grand Challenges Explorations
Cryptosporidium Infection
14 Jun 2017

Sumiti Vinayak of the University of Georgia in the U.S. will develop a genetic tool to rapidly turn genes off using light in order to study the function of essential genes in the intestinal parasite Cryptosporidium and accelerate drug discovery. Cryptosporidium causes chronic diarrhea and can lead to death in young children. There is currently only one drug available and it is not effective in many patients. New drugs can be developed based on a detailed understanding of the function of essential proteins, however this has been challenging in Cryptosporidium because it is not possible to control when a protein is degraded. They will develop a construct that fuses a protein of interest to a light-inducible domain carrying a hidden degradation signal. When exposed to blue light, this signal is activated, leading to protein degradation at a selected time. They will first optimize their system in vitro using the nanoluciferase gene and C. parvum sporozoites. They will then test it on a candidate essential protein by establishing a stable transgenic parasite cell line to infect mice. Oocysts containing the recombined constructs will then be isolated from the mice and used to infect a human intestinal cell line. After exposing these cells to blue light, they will use microscopy to analyze the effect of degrading the essential protein on the parasite’s life cycle.

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