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.
Iwnetim Abate and Loza Tadesse of SCIFRO Inc with Manu Prakash of Stanford University both in the U.S. will develop an education platform to inspire and equip African college students to solve local health problems through science using simple, inexpensive tools such as paper-based centrifuges and chemistry kits. Less than 8% of sub-Saharan Africans get to attend tertiary education, and there are limited options for pursuing a career in science. This means that even with the recent rise in inexpensive scientific equipment, many local problems of Africans remain unsolved. They will develop easy-to-follow pedagogy and teaching kits and use them to conduct a pilot study by holding a month-long summer workshop for 100 Ethiopian college students in Addis Ababa. The workshop will demystify the scientific process and motivate the students to begin tackling local projects, which will be monitored online. They will also invite 20 college instructors to participate and provide them with kits to distribute to their local schools and colleges.
Lemu Golassa of Addis Ababa University in Ethiopia and Laurent Dembele of University of Science, Techniques and Technology of Bamako in Mali will analyze the malaria-causing parasite Plasmodium vivax to identify molecules that enable it to transform into a dormant hypnozoite form in the liver, which is thought to be the key obstacle to malaria elimination. In many regions, P. vivax has become the dominant species causing malaria, resisting eradication due to this dormant liver stage of infection where it is resistant to most existing drugs and still a major cause of disease. Understanding how P. vivax forms hypnozoites could help develop more effective malaria drugs. They will isolate P. vivax from human blood and use cultured liver cells to evaluate their ability to form hypnozoites. Transcriptional profiling on these different isolates should reveal the molecular markers that enable P. vivax to form hypnozoites, which could be used as drug targets.
Philip Roessler of The College of William & Mary and Laiah Idelson of ETR both in the U.S. will test whether promoting cooperative mobile phone use in families in low-resource settings can improve household income and welfare. In their recent study, they found that providing a cost-free smartphone to poor households in Tanzania had a significant, positive impact on their economic state. The impact appeared to be catalyzed when both the male and female members of the household shared the smartphone and abolished when male members monopolized it. To investigate this, they will conduct a field study in Tanzania with 300 married young women. Two hundred women will be provided with smartphones, with half of those receiving specifically joint training also for their spouse on the use of digital banking and mobile money, to encourage cooperative use and knowledge-sharing within families. After 10-12 months, they will conduct surveys to evaluate whether cooperative use enhances economic status and health.
Clare Wenham of the London School of Economics and Political Science in the United Kingdom and colleagues will study whether considering gender in the design and operation of mosquito-control programs can help them to sustainably eliminate vector-borne diseases such as Zika. Brazil has eliminated disease-causing mosquitoes several times, but they keep returning. Data from Africa have shown that malaria control programs purposefully involving women have longer-lasting effects, which may translate to other countries and for other diseases. To test this, they will analyze how women impact vector control programs, as well as how they are specifically affected by them, by conducting fieldwork, including interviewing local community health workers and vector control agents, and analyzing existing data. This evidence will be used to produce a gender-mainstreamed vector control policy for piloting to test whether gender is a valuable determinant of the success of disease-control programs.
Lyle McKinnon of the University of Manitoba in Canada and Nicola Mulder of the University of Cape Town in South Africa will study the cause of bacterial vaginosis, which is linked to reproductive health complications and increased risk of HIV, to help identify new treatments. Bacterial vaginosis (BV) is characterized by harmful vaginal populations of anaerobic bacteria, often recurs, and is more common in Black and Latina women, suggesting that there could be a genetic component involved. Indeed, their previous genome-wide association study in South African women identified two human genetic variants associated with BV. These genes are involved in the epithelial-to-mesenchymal transition whereby epithelial cells lose their adhesion properties to become more like mesenchymal cells. To test whether this process is key to BV, and can thus be used to develop new treatments, they will expand their genome-wide association study and use in vitro cell models to analyze the role of the epithelial-to-mesenchymal transition in promoting the growth of harmful types of bacteria.
Yasmin Chandani of inSupply Health Limited and Pratap Kumar of Health-E-net Limited both in Kenya will develop a simple digital health tool to support the maternal and child health supply chains for low-literate, nomadic communities spread sparsely across Kenya. Counties in semi-arid lands have poor maternal and child health indicators caused by vast distances, low literacy rates, no fixed health facilities, and no data on supply chains. To address this, they will develop software to combine paper-based methods with feature-phone cameras for community health workers to easily record data on stocks and supplies. The recorded data will be integrated into existing workflows to inform supply chain managers and support ordering and resupply decisions. They will perform a twelve-month pilot study in Turkana County that will involve training community health workers to use the tool, and they will evaluate its performance in accurately recording stocks dispensed and received during resupply. They will also collect qualitative feedback from health workers to help improve the tools design.
Sunday Ekesi of the International Centre of Insect Physiology and Ecology in Kenya and Josh Tewskbury of Future Earth in the U.S. will model the effects of climate change on major food crops and their insect pests to better forecast crop yields and inform intervention strategies. The changing climate will likely have a multitude of effects on both insect-pest populations, by affecting their size and activity, and on crop physiology, which together will affect yield. They will dissect these complex interactions focusing on maize, which is the main staple food in Kenya, and a major maize-pest, and use a phytotron (enclosed research greenhouse) to evaluate the effects of the current climate, and a range of projected climates, on insect feeding rates and crop levels. These data will then be used in a process-based dynamic modelling approach to develop robust mathematical models that can make accurate predictions on crop loss caused by the climate.
Zaza Ndhlovu of the Africa Health Research Institute in South Africa and Fekadu Tafesse of Oregon Health & Science University (OHSU) will identify the molecular mechanisms enabling HIV to survive in humans to help develop new therapies to fully eradicate the disease. Potent antiretroviral therapies have rendered HIV a manageable chronic disease, but it is still incurable. Needing daily medication over a lifetime makes this approach ultimately expensive and also challenging to maintain in low-resource settings. The virus is thought to evade existing therapies by locating to lymph nodes where it is protected from being destroyed by CD8 T cells. CD8 T cells are banned from lymph nodes because they don't express the CXCR5 protein. They have discovered several epigenetic mechanisms that regulate CXCR5 levels. To follow up, they will screen 471 compounds that target epigenetic processes and may also upregulate CXCR5 in human primary CD8 T cells, and they will also test a known regulator of CXCR5 expression. Their results could lead to a gene therapy-based approach to cure HIV.
Seth Cochran of Operation Fistula in the U.S. and Nick Bennett of Simprints in the United Kingdom will incorporate facial recognition technology from Simprints into their existing automated patient registry to better track and support women with obstetric fistula in low-resource settings. Obstetric fistula is caused during childbirth and leads to the uncontrolled release of bodily wastes. It is estimated that more than 2 million young women live with untreated obstetric fistula in Asia and sub-Saharan Africa. They have set up a program to end fistula for every woman that has included developing a tablet or phone-based patient tracking and performance management system, which has been expanded to 15 countries. The challenge has been to accurately track individual patients from their initial identification through treatment to their managed reintegration into society. To address this, they will integrate and test two biometric technologies, fingerprinting and facial recognition, and evaluate their ability to accurately identify patients across different settings and people’s reactions to the technologies.
Justin Lessler of the International Vaccine Access Center, Baltimore of the Johns Hopkins University Bloomberg School of Public Health in the U.S. and Anthony Ahumibe of Nigeria Centre for Disease Control in Nigeria will launch a West African disease surveillance network for cholera to leverage local pathogen genome sequencing efforts for disease control and ultimately elimination. New genome sequencing technologies at substantially decreased costs have opened up the opportunity for laboratories in low-resource settings to monitor local disease by sequencing the genomes of the causative pathogens, which is critical for understanding disease epidemiology and guiding control efforts. However, these laboratories often lack the ability to analyze complex sequencing data. To address this, they will hold sequencing training workshops; provide equipment, reagents, and ongoing bioinformatic support; and establish a cross-country peer network using online collaborative tools. In addition, in response to the COVID-19 pandemic, support for SARS-CoV-2 sequencing will be provided to selected sites in the disease surveillance network.
Hamed Alemohammad of Open Imagery Network Inc. in the U.S. and Ernest Mwebaze of Google AI Research Center in Ghana will generate synthetic imaging data to train machine learning algorithms to better interpret satellite images in low-resource settings to monitor crops and increase food security. The increase in global satellite observations at different spatial and temporal scales has led to the development of sophisticated analytical methods such as machine learning for a variety of applications. For agricultural applications, the optimal performance of these methods requires ground reference data from field visits, which is time-consuming, expensive, and challenging in remote areas. To circumvent this need, they will generate a time series of realistic, fully synthetic images for around 8000 plots of major crops in Kenya using a generative adversarial networks approach, which involves developing two neural network models that compete against each other. They will then compare the synthetic imaging data with their existing ground reference data to see how well they can improve the classification of crop types using machine learning methods.
Mohlopheni Marakalala of the Africa Health Research Institute in South Africa and Eric Rubin of the Harvard TH Chan School of Public Health in the U.S. will use a genetic screening tool, Tn-seq, to identify the specific bacterial genes protecting Mycobacterium tuberculosis (MTB) from immune destruction that could be used to develop new therapeutic approaches to fight tuberculosis, which causes over 1.5 million deaths annually. BCG is the only approved tuberculosis vaccine, but its effect is limited, particularly in adults. This may be because BCG induces a memory-like innate immune response mediated by macrophages, so-called ‘trained immunity’, which the bacterium somehow evades. To find out how, they will use transposon-mediated mutagenesis to mutate every non-essential gene in MTB and use these mutant strains to infect BCG-trained monocytes isolated from vaccinated humans. The genes that enable MTB to survive under these conditions will then be identified by whole genome sequencing and validated using genetic and chemical approaches. This could ultimately lead to the development of targeted drugs to support BCG vaccinations.
Rudolph Gleason of Georgia Tech Research Corporation in the U.S. and Abebbaw Fekadu of CDT-Africa in Ethiopia will develop a low-cost, wearable device that wirelessly monitors the vital signs of neonates in low-resource settings to help lower mortality rates. In Ethiopia, and many other regions, the leading causes of neonatal deaths are respiratory distress, infection, and asphyxia. However, the key warning signs of these conditions - temperature, heart rate, respiratory rate, and blood oxygen concentration - are difficult to monitor in low-resource settings that often lack sufficient technical resources and medical staff. They have built a first-generation device that they will test on 50 neonates over seven days in a hospital in Addis Ababa to assess its performance in the clinic and gather user feedback from nurses and parents. Using the results, they will employ a user-centered design approach and engage Ethiopian engineering students to improve the device design and perform a market analysis and cost assessments for local manufacturing.
Stephan Sieber of the Technical University of Munich in Germany will work together with Véronique Dartois of Hackensack Meridian Health in the U.S. to test whether his new antibiotic, which uniquely activates, as well as inactivates, molecular pathways to destroy certain pathogenic bacteria, can be adapted to kill the related Mycobacterium tuberculosis (Mtb), which causes tuberculosis. Current antibiotic treatments are lengthy, and it remains difficult to completely destroy all the bacteria in the body. More worryingly is that Mtb has been developing resistance to these antibiotics, which all work in similar ways, so in some patients they are useless. They have discovered a new antibiotic that works differently: it inactivates bacterial menaquinone biosynthesis but also uniquely activates a signal peptidase to boost its secretory function. In the laboratory, this antibiotic notably bypasses the development of resistance and even kills dormant bacteria, likely by its activating mechanism. They will investigate its mechanism of action in Mtb using affinity-based protein profiling and use that knowledge to select related compounds that might work better in people. These will then be tested in a mouse model of tuberculosis as a first step towards clinical development.
David Hughes of Pennsylvania State University, John Corbett of aWhere, and Rhiannan Price of DigitalGlobe, in the U.S. will develop a software platform comprising prediction algorithms that leverage artificial intelligence to predict where and when plant diseases and pests will occur from weather and satellite data to alert farmers to check their crops. Pests and diseases are moving targets, however most current surveillance methods monitor only their presence or absence. Predicting when and where they are likely to occur would be more valuable for preventing them. This has recently been made possible by studies on how environmental factors influence the emergence and behaviour of crop pests and diseases. They will use a systems approach that incorporates these new predictors along with historical data and couples them with an artificial intelligence component that learns from ground observations recorded using smartphones to improve accuracy. They will combine their existing agricultural intelligence platform and smartphone application with their prototype predictive model and test their approach with maize and cassava crops on farms across seven different counties in Kenya. The platform will produce location-specific forecasts that can be acted upon immediately by farmers.
David Aanensen from the University of Oxford and the Wellcome Sanger Institute in the United Kingdom and Maria van Kerkhove of the World Health Organization in Switzerland will combine next generation DNA sequencing technology with a simple, web-based data collection, processing, and distribution platform to better track the global spread of deadly infectious diseases including Middle East Respiratory Syndrome (MERS-CoV). MERS - also known as camel flu - is a viral disease that causes fever, cough, diarrhea, and shortness of breath, and is transmitted from camels to humans. One third of people diagnosed with the disease die. Next generation sequencing (NGS) technology allows rapid, inexpensive detection of pathogens as they spread. However, laboratories in different member states use different formats for sequencing data, and there is no mechanism for sharing it in real time. This limits the value of the technology for stopping outbreaks. To address this, they will establish routine sequencing protocols for both human and camel samples, and develop an interactive web platform on which the sequencing and epidemiological data can be shared. This will help develop more effective, real-time medical and non-medical interventions at local, national, and international levels. Once established, the protocols developed here may be applied to outbreaks of other diseases.
Achim Hoerauf of IMMP in Germany will apply artificial intelligence (AI) to speed the development of treatments for onchocerciasis, which is an infectious disease commonly known as River Blindness caused by a parasitic worm. The parasites are spread by affected blackflies, and the worm larvae accumulate in the skin and eyes, causing irritation and sometimes blindness. Nearly 21 million cases occur each year, and 99% of affected people live in Africa. The drug currently used for treatment kills only worm larvae, and studies are ongoing to identify more effective drugs that target adult worms. However, evaluating these drug candidates requires manual analysis using microscopy of samples of irritated skin from patients after treatment. This process is time consuming and slows drug development. To address this, they will use samples that have already been manually annotated to train an AI system to automatically analyze future samples to recognize worm body parts, gender, vitality, and stage of development. Once established, the AI system will be tested with samples from a new clinical trial - tissues from patients treated with the new drug will be analyzed in parallel by human and computer. Once optimized, the AI system will take over the analysis, and the much slower human analysis will only be needed as a quality control system.
Yingda Xie of Rutgers, The State University of NJ and JoAnne Flynn of the University of Pittsburgh, both in the U.S., will develop a non-invasive approach for testing candidate anti-tuberculosis compounds in animal models and patients using positron emission tomography-x-ray computed tomography (PET/CT). Tuberculosis (TB) is a leading cause of death in developing countries, and rates are sustained by the causative bacterium, Mycobacterium tuberculosis, developing resistance to current drugs. To circumvent this, new drugs are being designed to target human cells and proteins rather than those of the bacteria. To test these drugs, new tools are also needed to monitor TB in patients. 18 Fluorodeoxyglucose (FDG)-PET/CT is a non-invasive imaging tool that uses radioactively-labelled glucose to light up areas of metabolic activity in the body such as the lesions formed by M. tuberculosis and immune cells that play a critical role in infection. They have histopathological sections and cell and chemical data of TB lesions from non-human primate models and will use them to quantify the different lesions. Then, by using the available PET-CT scans of the lesions, they will search for quantitative signatures that can predict a specific type of lesion. The accuracy of these PET/CT signatures will be tested in a separate group of animals. Their study will reveal details of the TB immune response across different lesions, which could help design new treatments, and the signatures can be used to test the activity of new drug candidates in animal models and humans.
Alain Labrique of Johns Hopkins Bloomberg School of Public Health in the U.S. and Meghan Azad of the University of Manitoba in Canada will study the impact of prelacteals - fluids or solids given before breastfeeding is established - on the populations of bacteria in the newborn gut (the microbiome), and how it may affect development. Immediate and exclusive breastfeeding helps maintain healthy growth in infants and protects them against infections, which are also influenced by their gut microbiome. However, in Bangladesh and many other low-resource countries, it is common practice to give newborns ritual foods, like honey or sugar water, before breastfeeding begins, which may impede development. They hypothesize a link between prelacteal use and newborn development mediated by the gut microbiome. To test this, they will use an ongoing population-based study in rural Bangladesh and compare the types and amounts of bacteria in the gut using stool samples of 300 prelacteal-fed and exclusively breastfed infants at 7 days, 28 days and 3 months of life. They will also analyze the composition of the prelacteals being used, including the presence of any toxic contaminants, and of the breastmilk of the mothers, for correlating with any changes in gut microbial populations. The study will enable them to quantify the potentially negative impact of this widespread cultural practice, common to over a billion people across the Gangetic floodplain.
Eric Kaduru of KadAfrica Estate Limited and John Onekalit of the Kitgum Concerned Women's Association both in Uganda will provide a 12-month, integrated life skills and agricultural training program along with land and seedlings to young refugee women out of school in Uganda to begin their own sustainable passion fruit farming cooperatives. Uganda has accepted many refugees, but also has the world's youngest population and very high unemployment. As a result, particularly girls have very limited employment opportunities if they even manage to finish school, and instead often work in the sex industry or immediately get married. This in turn leads to increased teenage pregnancies and rates of HIV. They will provide a cooperative start-up kit including training in sustainable passion fruit farming, which has a guaranteed market, access to land through a community-based land lease model, and passion fruit seedlings. The girls will also be taught about finance, nutrition, and sexual and reproductive health. They will test their approach in two refugee camps with 180 adolescent girls between 14- and 22-years old who are out of school. The success of the project will be assessed in terms of the effect on poverty and health.
Ruth Müller of the Institute of Tropical Medicine in Belgium and Meghnath Dhimal of the Nepal Health Research Council will provide entomological training for health science students and medical professionals and increase community awareness of vector-borne diseases (VBDs) in Nepal to better equip the population to deal with disease outbreaks. VBDs like those caused by the dengue, zika, or chikungunya viruses cause more than 700,000 deaths annually, mostly in poor countries with limited public health resources and tropical climates. Climate change has expanded the affected areas as warmer temperatures facilitate survival of the insect vectors. They will establish the EntoCAP team to enhance entomological capacity to fight these diseases. The team will hold five-day workshops for 300 health science students and health care professionals on surveillance and control of vector populations, and monitoring of disease outbreaks. They will also increase community interest in VBDs by hosting science labs for children to teach them how to recognize mosquitoes at various developmental stages and understand the dangers of VBDs. In addition, they will begin building a reference collection using DNA barcoding technology to catalog insect vectors by species for studying biodiversity and microevolution of disease vectors.
Elena Levashina of the Max Planck Institute for Infection Biology in Germany and Kelly Lee of the University of Washington in the U.S. will use cryoelectron tomography to image the three-dimensional ultrastructure of a protein on the surface of the malaria-causing parasite Plasmodium falciparum to help design better vaccines. Malaria kills half a million people annually, but there are still no highly effective vaccines available. One of the parasite's coat proteins, CSP, is a prime target for vaccine development. However, not much is known about its natural structure on the live parasite, which is how inhibitory antibodies produced in response to a vaccine will be able to recognize and destroy it. One of the best ways to observe the natural structure of a protein at high resolution is to immobilize it in non-crystalline ice and image it under very low (< −150 °C) temperatures. They will develop protocols to isolate large numbers of highly pure parasites directly from mosquitoes and carefully cryopreserve them on grids to maintain their natural form and enable clearer imaging. They will also use this high-resolution imaging technique to study how antibody binding affects the parasite. Their results will help design new vaccines that can produce highly active, inhibitory antibodies.
Eric Ochomo of the Kenya Medical Research Institute (KEMRI) in Kenya and Luc Djogbenou of the University of Abomey (UAC) in Benin will develop a curriculum to teach African scientists how to use genetic approaches to combat insecticide resistance in the fight against malaria. Malaria is a disease that kills almost 500,000 people annually, most in sub-Saharan Africa. People become infected when bitten by mosquitoes that transmit the disease-causing parasites. Insecticide treatment of bed nets and indoor areas are effective methods of disease control, but mosquitoes are becoming resistant. Varying the types of insecticides used and applying them in different combinations can help fight resistance, but it's difficult to know the most effective approach before resistance develops without the help of genetic markers. They will teach African scientists techniques to identify genetic resistance markers including sample collection and preservation, transcriptomic and whole-genome sequencing, and bioinformatics using online and hands-on approaches. This will ensure timely changes to insecticide application to better combat resistance. They will also encourage local scientists to establish industry partnerships to ensure that resistance monitoring can continue long-term.
Sophie Mower of The Centre for Global Equality in the United Kingdom will establish a collaborative program for technology students at Bahir Dar University in Ethiopia using expertise and support from a number of other centers in Africa and beyond to provide training and financial resources for them to research and develop their own innovative solutions to local challenges. Students at the university work on creative solutions such as mapping applications particularly in areas of agriculture and health. However, advancing their ideas is limited by the lack of professional networks and material resources. They will provide a dedicated space at the university and work with the Centre for Global Equality (CGE) and companies in the Cambridge Cluster, both in the United Kingdom, and an African innovation hub. Together, they will provide training for 30 students on co-creating their solutions with end-users to increase their impact. They will also hold an ideation hackathon to generate design ideas, and award $2000 to the six most competitive projects. These will be supported through to prototype development using methods from an incubator approach established at the CGE.
Cambria Finegold, Richard Shaw and Roger Day of the Centre for Agriculture and Bioscience International in collaboration with Katherine Derby of the University of York and Sarah Gurr of the University of Exeter all in the United Kingdom, will design a platform - GBCrop - to collect, analyze and disseminate data on the global impact of crop pests and disease. The fact that 40% of crops are lost to pests impacts both the global food supply and local economies. Despite this, little is known about why and how crop pests and diseases occur. The extent of the problem was acknowledged by the UN declaring 2020 the Year of the Plant. They will design GBCrop to collect large quantities of high-quality data and apply advanced analytical methods to generate results that can then be used to direct research and policy development, and to predict the impact of emerging diseases. The program is modeled after Global Burden of Disease, which has transformed health policy agendas over the last 25 years. They will begin by consulting with key experts, and then include policy makers, private industry representatives, government organizations, potential funders and scientific experts. Together they will decide what data to collect and how it can best be used to accurately predict the impact of emerging crop diseases. They will launch their plan-of-action in the Year of the Plant and aim to make their first recommendations in 2023 on how to maximize crop gains.
Mohlopheni Marakalala of the Africa Health Research Institute in South Africa will study the role of specific proteins associated with immune cell death in tuberculosis patients to better understand how the disease progresses and help develop new diagnostics and therapies. Tuberculosis (TB) is a bacterial disease that causes 1.5 million deaths per year, mostly in poor countries. Understanding how the human immune system responds to TB infection could help develop more effective, host-targeted treatments. Granulomas - tissues that form as a result of inflammation - are commonly seen in the lungs of TB patients. Their characteristics change as the disease progresses and they can cause severe lung damage. Granulomas are thought to be formed by the death of white blood cells called neutrophils, which are also abundant in the airways of patients. He will study granulomas isolated from patients at different stages of the disease to identify proteins linked to neutrophil cell death and see if they are linked with lung damage and disease progression. He will then determine whether the levels of these proteins in the blood can be used as disease biomarkers for the early detection of TB. Lastly, he will use molecular genetic techniques to reduce the level of these proteins in neutrophils and evaluate the effect on TB infection to see if the approach could be exploited as a potential therapy.
Iruka Okeke of the University of Ibadan, College of Medicine in Nigeria and Kat Holt of Monash University in Australia will set-up a remote laboratory that uses nanopore sequencing as a low-cost, portable method to monitor the spread of antimicrobial resistance in rural areas of Africa and combine it with genome editing tools for more rapid diagnosis and improved treatment. Antimicrobial resistance (AMR) occurs when pathogens are able to survive treatments that previously would have killed them. Infection persists in these patients and spreads to others in the community, increasing both the risk of serious complications and the economic costs. To combat AMR, it needs to be tracked locally and quickly enough to inform treatment. However, traditional tracking methods are slow, and difficult to use in rural settings because of limited resources. Nanopore sequencing technology is a highly portable method of sequencing DNA that is suitable for resource-poor settings. They will setup a prototype minimal bacterial genomics lab at a provincial hospital laboratory in Africa, and use nanopore sequencing to catalog pathogens collected from patients and monitor AMR. They will also combine the sequencing with a genome editing tool - CRISPR-Cas - to enrich for known resistant pathogens and enable much faster diagnosis directly from blood or stool samples. Once optimized in the initial location, the remote lab can be recreated in other areas of Africa.
Caroline Stefani of the Benaroya Research Institute at Virginia Mason and Yongxing (Leon) Zhao of Carnegie Mellon University both in the U.S. will build an imaging platform combining expansion microbiology and confocal virtual reality to visualize complex host-pathogen interactions in infected tissues to help develop new diagnostics and therapeutics. It is the molecular interactions between the host and the pathogen, both in tissues and inside cells, that ultimately dictate whether an infection takes hold or is destroyed. Identifying these interactions could help develop new treatments. However, they remain difficult to study in sufficient resolution. They have developed a new method for three-dimensional visualization of confocal microscopy images using commercial virtual reality technology to pinpoint the subcellular localization of host-pathogen interactions. They will combine this with a new technique, expansion microscopy optimized for microbiology (ExMicro), which visualizes nanoscale details of dozens of different molecules in infected tissue by embedding it in a polyacrylate-based polymer that can be expanded in pure water to improve resolution. They will develop protocols and software to optimize both methods for studying host-pathogen interactions, and build a platform to share their new toolset with the scientific community.
Pia Wintermark of McGill University in Canada and Cally Tann of the London School of Hygiene & Tropical Medicine in the United Kingdom will establish a pilot cohort in Uganda of term newborns who suffered from asphyxia at birth, which means that their brain and other organs did not receive enough blood or oxygen, and conduct a clinical test of a novel neurorestorative agent (i.e., to repair brain injuries) to see if it can improve early brain development in this setting. Birth asphyxia and the resulting neonatal encephalopathy is the third leading cause of mortality in infants under five and leads to significant brain damage and long-term neurodevelopmental morbidities. In a rat model of term neonatal brain damage, they found that a compound, sildenafil, reduced brain damage and inflammation, and increased nerve cell growth. This compound has already proven safe for use in humans for other purposes. They will first assemble a pilot cohort of 100 neonates with neonatal encephalopathy in Uganda, and clinically evaluate them over the first three months of age to better characterize the disease in this setting. From this cohort, 30 newborns will be selected to test whether daily treatment of sildenafil from day 2 to day 9 of life can improve brain growth and development and is a feasible and acceptable neurorestorative treatment strategy in this setting.
Anne CC Lee and Mandy Brown Belfort of Brigham and Women's Hospital in the U.S. along with Stéphane Sizonenko and Petra Huppi of the University of Geneva in Switzerland will test whether lactoferrin, a breast milk nutrient, can promote growth and reduce injury in the developing infant brain. Of the 15 million annual preterm births, almost a million of the surviving babies have severe neurological defects such as cerebral palsy. However, there are limited treatments available. Breast milk has a positive effect on the infant brain, but the mechanisms for this are unclear. Their preliminary data showed that lactoferrin, a glycoprotein found in breast milk, has a neuroprotective effect in several rat models of neonatal brain injury. They will build on this to study the effect of different concentrations of lactoferrin in the rat models, as well as assaying candidate inflammation, cell death, and neurotrophic factors to identify the molecular mechanisms involved. They will perform a human observational study to associate the different levels of lactoferrin found in breast milk samples from a cohort of mothers of preterm infants at Brigham and Women's Hospital with the infant's brain development as assessed by magnetic resonance imaging. They will also measure lactoferrin levels in samples collected from 100 mothers in Bangladesh to see how they compare. Together, they will generate essential data on lactoferrin for future human clinical trials in low- to middle-income countries.
Alison Bentley of the National Institute of Agricultural Botany and Ari Sadanandom of the University of Durham both in the United Kingdom will examine whether a new molecular link that they found explaining the increase in plant diseases (biotic factors) associated with high nutrient levels (abiotic factors) can be exploited to maximize wheat crop yield with minimal negative impact on the environment. Wheat, one of the first domesticated food crops, has been grown for over 10,000 years and is critically important to global food supply. Traditionally, crop yields are maximized by applying nitrogen fertilizer to stimulate growth, and fungicides and pesticides to prevent disease. These approaches are expensive and can harm the environment. Another complication is that increasing amounts of nitrogen fertilizer also increases the occurrence of disease. They have identified a group of transcription factors (TFs) - proteins that control expression of specific genes – that appear to protect plants against the fungus Septoria specifically under varying nitrogen levels. To investigate this, they will create transgenic wheat to increase or decrease each TF and explore the effect on disease resistance and growth in different concentrations of nitrogen. Understanding this relationship will allow them to boost plant resistance to disease under high growth conditions, and thereby optimize crop yield with maximal economic gain and minimal environmental impact.