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Study in Africa Yields New Diabetes Gene

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Francis Collins Volunteering in Nigeria
Caption: Volunteering my medical services in Nigeria three decades ago inspired me to learn more about type 2 diabetes in Africa and beyond. Credit: Margaret Collins

When I volunteered to serve as a physician at a hospital in rural Nigeria more than 25 years ago, I expected to treat a lot of folks with infectious diseases, such as malaria and tuberculosis. And that certainly happened. What I didn’t expect was how many people needed care for type 2 diabetes (T2D) and the health problems it causes. Surprisingly, these individuals were generally not overweight, and the course of their illness seemed different than in the West.

The experience inspired me to join with other colleagues at Howard University, Washington, DC, to help found the Africa America Diabetes Mellitus (AADM) study. It aims to uncover genomic risk factors for T2D in Africa and, using that information, improve understanding of the condition around the world.

So, I’m pleased to report that, using genomic data from more than 5,000 volunteers, our AADM team recently discovered a new gene, called ZRANB3, that harbors a variant associated with T2D in sub-Saharan Africa [1]. Using sophisticated laboratory models, the team showed that a malfunctioning ZRANB3 gene impairs insulin production to control glucose levels in the bloodstream.

Since my first trip to Nigeria, the number of people with T2D has continued to rise. It’s now estimated that about 8 to 10 percent of Nigerians have some form of diabetes [2]. In Africa, diabetes affects more than 7 percent of the population, more than twice the incidence in 1980 [3].

The causes of T2D involve a complex interplay of genetic, environmental, and lifestyle factors. I was particularly interested in finding out whether the genetic factors for T2D might be different in sub-Saharan Africa than in the West. But at the time, there was a dearth of genomic information about T2D in Africa, the cradle of humanity. To understand complex diseases like T2D fully, we need all peoples and continents represented in the research.

To begin to fill this research gap, the AADM team got underway and hasn’t looked back. In the latest study, led by Charles Rotimi at NIH’s National Human Genome Research Institute, in partnership with multiple African diabetes experts, the AADM team enlisted 5,231 volunteers from Nigeria, Ghana, and Kenya. About half of the study’s participants had T2D and half did not.

As reported in Nature Communications, their genome-wide search for T2D gene variants turned up three interesting finds. Two were in genes previously linked to T2D risk in other human populations. The third involved a gene that codes for ZRANB3, an enzyme associated with DNA replication and repair that had never been reported in association with T2D.

To understand how ZRANB3 might influence a person’s risk for developing T2D, the researchers turned to zebrafish (Danio rerio), an excellent vertebrate model for its rapid development. The researchers found that the ZRANB3 gene is active in insulin-producing beta cells of the pancreas. That was important to know because people with T2D frequently have reduced numbers of beta cells, which compromises their ability to produce enough insulin.

The team next used CRISPR/Cas9 gene-editing tools either to “knock out” or reduce the expression of ZRANB3 in young zebrafish. In both cases, it led to increased loss of beta cells.

Additional study in the beta cells of mice provided more details. While normal beta cells released insulin in response to high levels of glucose, those with suppressed ZRANB3 activity couldn’t. Together, the findings show that ZRANB3 is important for beta cells to survive and function normally. It stands to reason, then, that people with a lower functioning variant of ZRANB3 would be more susceptible to T2D.

In many cases, T2D can be managed with some combination of diet, exercise, and oral medications. But some people require insulin to manage the disease. The new findings suggest, particularly for people of African ancestry, that the variant of the ZRANB3 gene that one inherits might help to explain those differences. People carrying particular variants of this gene also may benefit from beginning insulin treatment earlier, before their beta cells have been depleted.

So why wasn’t ZRANB3 discovered in the many studies on T2D carried out in the United States, Europe, and Asia? It turns out that the variant that predisposes Africans to this disease is extremely rare in these other populations. Only by studying Africans could this insight be uncovered.

More than 20 years ago, I helped to start the AADM project to learn more about the genetic factors driving T2D in sub-Saharan Africa. Other dedicated AADM leaders have continued to build the research project, taking advantage of new technologies as they came along. It’s profoundly gratifying that this project has uncovered such an impressive new lead, revealing important aspects of human biology that otherwise would have been missed. The AADM team continues to enroll volunteers, and the coming years should bring even more discoveries about the genetic factors that contribute to T2D.

References:

[1] ZRANB3 is an African-specific type 2 diabetes locus associated with beta-cell mass and insulin response. Adeyemo AA, Zaghloul NA, Chen G, Doumatey AP, Leitch CC, Hostelley TL, Nesmith JE, Zhou J, Bentley AR, Shriner D, Fasanmade O, Okafor G, Eghan B Jr, Agyenim-Boateng K, Chandrasekharappa S, Adeleye J, Balogun W, Owusu S, Amoah A, Acheampong J, Johnson T, Oli J, Adebamowo C; South Africa Zulu Type 2 Diabetes Case-Control Study, Collins F, Dunston G, Rotimi CN. Nat Commun. 2019 Jul 19;10(1):3195.

[2] Diabetes mellitus in Nigeria: The past, present and future. Ogbera AO, Ekpebegh C. World J Diabetes. 2014 Dec 15;5(6):905-911.

[3] Global report on diabetes. Geneva: World Health Organization, 2016. World Health Organization.

Links:

Diabetes (National Institute of Diabetes ad Digestive and Kidney Diseases/NIH)

Diabetes and African Americans (Department of Health and Human Services)

Why Use Zebrafish to Study Human Diseases (Intramural Research Program/NIH)

Charles Rotimi (National Human Genome Research Institute/NIH)

NIH Support: National Human Genome Research Institute; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute on Minority Health and Health Disparities


Targeting the Microbiome to Treat Malnutrition

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Caption: A Bangladeshi mother and child in the Nutritional Rehabilitation Unit.
Credit: International Centre for Diarrhoeal Disease Research, Bangladesh

A few years ago, researchers discovered that abnormalities in microbial communities, or microbiomes, in the intestine appear to contribute to childhood malnutrition. Now comes word that this discovery is being translated into action, with a new study showing that foods formulated to repair the “gut microbiome” may help malnourished kids rebuild their health [1].

In a month-long clinical trial in Bangladesh, 63 children received either regular foods to treat malnutrition or alternative formulations for needed calories and nutrition that also encouraged growth of beneficial microbes in the intestines. The kids who ate the microbiome-friendly diets showed improvements in their microbiome, which helps to extract and metabolize nutrients in our food to help the body grow. They also had significant improvements in key blood proteins associated with bone growth, brain development, immunity, and metabolism; those who ate standard therapeutic food did not experience the same benefit.

Globally, malnutrition affects an estimated 238 million children under the age 5, stunting their normal growth, compromising their health, and limiting their mental development [2]. Malnutrition can arise not only from a shortage of food but from dietary imbalances that don’t satisfy the body’s need for essential nutrients. Far too often, especially in impoverished areas, the condition can turn extremely severe and deadly. And the long term effects on intellectual development can limit the ability of a country’s citizens to lift themselves out of poverty.

Jeffrey Gordon, Washington University School of Medicine in St. Louis, and his NIH-supported research team have spent decades studying what constitutes a normal microbiome and how changes can affect health and disease. Their seminal studies have revealed that severely malnourished kids have “immature” microbiomes that don’t develop in the intestine like the microbial communities seen in well nourished, healthy children of the same age.

Gordon and team have also found that this microbial immaturity doesn’t resolve when kids consume the usual supplemental foods [3]. In another study, they turned to mice raised under sterile conditions and with no microbes of their own to demonstrate this cause and effect. The researchers colonized the intestines of the germ-free mice with microbes from malnourished children, and the rodents developed similar abnormalities in weight gain, bone growth, and metabolism [4].

All of this evidence raised a vital question: Could the right combination of foods “mature” the microbiome and help to steer malnourished children toward a healthier state?

To get the answer, Gordon and his colleagues at the International Centre for Diarrhoeal Disease Research, Dhaka, Bangladesh, led by Tahmeed Ahmed, first had to formulate the right, microbiome-friendly food supplements, and that led to some interesting science. They carefully characterized over time the immature microbiomes found in Bangladeshi children treated for severe malnutrition. This allowed them to test their new method for analyzing how individual microbial species fluctuate over time and in relationship to one another in the intestine [5]. The team then paired up these data with measurements of a set of more than 1,300 blood proteins from the children that provide “readouts” of their biological state.

Their investigation identified a network of 15 bacterial species that consistently interact in the gut microbiomes of Bangladeshi children. This network became their means to characterize sensitively and accurately the development of a child’s microbiome and/or its relative state of repair.

Next, they turned to mice colonized with the same collections of microbes found in the intestines of the Bangladeshi children. Gordon’s team then tinkered with the animals’ diets in search of ingredients commonly consumed by young children in Bangladesh that also appeared to encourage a healthier, more mature microbiome. They did similar studies in young pigs, whose digestive and immune systems more closely resemble humans.

The Gordon team settled on three candidate microbiome-friendly formulations. Two included chickpea flour, soy flour, peanut flour, and banana at different concentrations; one of these two also included milk powder. The third combined chickpea flour and soy flour. All three contained similar amounts of protein, fat, and calories.

The researchers then launched a randomized, controlled clinical trial with children from a year to 18 months old with moderate acute malnutrition. These young children were enrolled into one of four treatment groups, each including 14 to 17 kids. Three groups received one of the newly formulated foods. The fourth group received standard rice-and-lentil-based meals.

The children received these supplemental meals twice a day for four weeks at the International Centre for Diarrhoeal Disease Research followed by two-weeks of observation. Mothers were encouraged throughout the study to continue breastfeeding their children.

The formulation containing chickpea, soy, peanut, and banana, but no milk powder, stood out above the rest in the study. Children taking this supplement showed a dramatic shift toward a healthier state as measured by those more than 1,300 blood proteins. Their gut microbiomes also resembled those of healthy children their age.

Their new findings published in the journal Science offer the first evidence that a therapeutic food, developed to support the growth and development of a healthy microbiome, might come with added benefits for children suffering from malnutrition. Importantly, the researchers took great care to design the supplements with foods that are readily available, affordable, culturally acceptable, and palatable for young children in Bangladesh.

A month isn’t nearly long enough to see how the new foods would help children grow and recover over time. So, the researchers are now conducting a much larger study of their leading supplement in children with histories of malnutrition, to explore its longer-term health effects for them and their microbiomes. The hope is that these new foods and others adapted for use around the world soon will help many more kids grow up to be healthy adults.

References:

[1] Effects of microbiota-directed foods in gnotobiotic animals and undernourished children. Gehrig JL, Venkatesh S, Chang HW, Hibberd MC, Kung VL, Cheng J, Chen RY, Subramanian S, Cowardin CA, Meier MF, O’Donnell D, Talcott M, Spears LD, Semenkovich CF, Henrissat B, Giannone RJ, Hettich RL, Ilkayeva O, Muehlbauer M, Newgard CB, Sawyer C, Head RD, Rodionov DA, Arzamasov AA, Leyn SA, Osterman AL, Hossain MI, Islam M, Choudhury N, Sarker SA, Huq S, Mahmud I, Mostafa I, Mahfuz M, Barratt MJ, Ahmed T, Gordon JI. Science. 2019 Jul 12;365(6449).

[2] Childhood Malnutrition. World Health Organization

[3] Persistent gut microbiota immaturity in malnourished Bangladeshi children. Subramanian S, Huq S, Yatsunenko T, Haque R, Mahfuz M, Alam MA, Benezra A, DeStefano J, Meier MF, Muegge BD, Barratt MJ, VanArendonk LG, Zhang Q, Province MA, Petri WA Jr, Ahmed T, Gordon JI. Nature. 2014 Jun 19;510(7505):417-21.

[4] Gut bacteria that prevent growth impairments transmitted by microbiota from malnourished children. Blanton LV, Charbonneau MR, Salih T, Barratt MJ, Venkatesh S, Ilkaveya O, Subramanian S, Manary MJ, Trehan I, Jorgensen JM, Fan YM, Henrissat B, Leyn SA, Rodionov DA, Osterman AL, Maleta KM, Newgard CB, Ashorn P, Dewey KG, Gordon JI. Science. 2016 Feb 19;351(6275).

[5] A sparse covarying unit that describes healthy and impaired human gut microbiota development. Raman AS, Gehrig JL, Venkatesh S, Chang HW, Hibberd MC, Subramanian S, Kang G, Bessong PO, Lima AAM, Kosek MN, Petri WA Jr, Rodionov DA, Arzamasov AA, Leyn SA, Osterman AL, Huq S, Mostafa I, Islam M, Mahfuz M, Haque R, Ahmed T, Barratt MJ, Gordon JI. Science. 2019 Jul 12;365(6449).

Links:

Childhood Nutrition Facts (Centers for Disease Control and Prevention)

Gordon Lab (Washington University School of Medicine in St. Louis)

NIH Human Microbiome Project

International Centre for Diarrhoeal Disease Research (Dhaka, Bangladesh)

NIH Support: National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of General Medical Sciences; National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Center for Advancing Translational Sciences; National Cancer Institute


With 2019 Class of Global Health Fellows

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With the 2019 Class of Global Health Fellow
I enjoyed taking part in NIH’s Fogarty International Center’s Global Health Fellows Orientation on July 2, 2019. Held on the NIH campus, the orientation allowed me to meet this year’s impressive class from the Global Health Program for Fellows and Scholars. This NIH program supports six U.S. university consortia, which provide collaborative, mentored global health research training in low- and middle-income countries. Individual students, postdoctoral fellows, or faculty from the U.S. and abroad apply through the consortia to spend a year at an institution in a low- and middle-income country. Courtesy of Kristen Weymouth

Farrar Delivers Barmes Lecture

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Francis Collins and Jeremy Farrar
Jeremy Farrar (left), director of the Wellcome Trust, London, delivered the 2019 David E. Barmes Global Health Lecture on June 19 in NIH’s Masur Auditorium. The lecture was titled, “Global Health in a Changing World.” Jeremy also presented me with a copy of the just-released Wellcome Global Monitor 2018. It offers the results of Wellcome’s survey of 140,000 people worldwide about science and global health challenges. The inside front cover included his handwritten inscription, which he asked me to read aloud to the audience, “Francis and all colleagues and friends at the N.I.H. We admire, respect, and give all our thanks for your leadership and friendship. Very best wishes, Jeremy.” The annual lecture honors the late David Edward Barmes, special expert for international health in the NIH’s National Institute of Dental and Craniofacial Research (NIDCR). The NIDCR cosponsors the Barmes Lecture with NIH’s Fogarty International Center. Credit: Marleen Van den Neste.

Combating Mosquitoes with an Engineered Fungus

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Caption: Anopheles coluzzii mosquito with transgenic fungus (green) emerging from its body after death. Credit: Brian Lovett, University of Maryland, College Park

Almost everywhere humans live on this planet, mosquitoes carry microbes that cause potentially deadly diseases, from West Nile virus to malaria. While chemical insecticides offer a line of defense, mosquito populations often grow resistant to them. So, it’s intriguing to learn that we may now have another ally in this important fight: a genetically engineered fungus!

Reporting in the journal Science, an international research team supported by NIH describes how this new approach might be used to combat malaria [1]. A fungus called Metarhizium pingshaense is a natural enemy of the mosquito, but, by itself, it kills mosquitoes too slowly to control transmission of malaria. To make this fungus an even more efficient mosquito killer, researchers engineered it to carry a gene encoding a toxin, derived from a spider, that is deadly to insects. Tests of the souped-up fungus in a unique contained facility designed to simulate a West African village found it safely and rapidly killed insecticide-resistant mosquitoes, reducing their numbers by more than 99 percent within 45 days.

Mosquitoes are the deadliest animals in the world. More than 3.2 billion people—about half of all humans—are at risk for malaria, and more than 400,000 die each year from the disease. Other mosquito-borne illnesses, including Zika and dengue viruses, sicken millions more each year. By combining existing insect control strategies with the latest technical innovation, it should be possible to lower those numbers.

In the latest study, Raymond St. Leger and Brian Lovett, University of Maryland, College Park, teamed with Abdoulaye Diabate and colleagues from Institut de Recherche en Sciences de la Santé/Cente Muraz, Burkina Faso, West Africa. The researchers employed a strategy that’s been in use around the world for more than 100 years to control agricultural pests.

The approach involves the fungal species Metarhizium, which kills a variety of insects. Earlier studies had shown that spores from a specific Metarhizium strain could make a big enough dent in a mosquito population to raise the possibility of using the fungus to reduce infective bites among humans [2]. But killing off the mosquitoes required very large quantities of fungal spores and usually took a couple of weeks.

Here’s where things turned innovative. To boost the fungus’s potency, St. Leger and colleagues used genetic engineering to add a toxin derived from the Australian Blue Mountains funnel-web spider. The toxin came with a major advantage: the U.S. Environmental Protection Agency (EPA) already has approved its use as a safe-and-effective insecticidal protein.

Besides giving the engineered fungus that ability to produce a spider toxin, the researchers added another clever element. They didn’t want the fungus to produce the toxin all the time—only after it comes in contact with a mosquito’s hemolymph, the insect equivalent of blood. So, they needed to insert a control switch, and the researchers knew just where to find the needed part.

Once inside a mosquito, the fungus naturally produces a structural protein called collagen that shields it from the insect’s immune system. A genetic switch that turns “on” when it detects an insect’s hemolymph controls that collagen production. To ensure that the spider toxin was produced at just the right time, the researchers hotwired their Metarhizium to begin producing it under the control of this same genetic switch.

The next step was to test this modified organism in a more natural, but controlled, environment. The researchers spent more than a year in Burkina Faso building a specialized facility called a MosquitoSphere. It’s similar to a very large greenhouse, but with mosquito netting instead of glass.

The MosquitoSphere has six separate compartments, four of which contain West African huts, along with native plants and breeding sites for mosquitoes. The researchers hung a black cotton sheet, previously soaked in sesame oil, on the wall of a hut in each of three chambers.

In one hut, the sesame oil contained genetically engineered fungal spores. In the second hut, the oil contained natural fungal spores. In the third hut, there were no spores at all. Then, they released 1,000 adult male and 500 adult female mosquitoes into each chamber and watched what happened over the next 45 days.

In the hut without spores, the mosquitoes established a stable population of almost 1,400. In the chamber with the natural spores, 450 mosquitoes survived. But, in the chamber with the engineered fungus, the researchers counted just 13 survivors—too few to sustain a viable population.

The researchers say they suspect the fungus would be relatively easy to contain in nature. It’s sticky and not easily airborne. The spores are also extremely sensitive to sunlight, making it difficult for them to travel far. Importantly, the fungus didn’t harm other beneficial insects, including honeybees.

Caution is warranted before considering the release of a genetically engineered organism into the wild. In the meantime, the genetically engineered fungus also will serve as a platform for continued technology development.

The system can be readily adapted to target mosquitoes or other insects , perhaps using different natural toxins if insects might grow resistant to Metarhizium just as they have to traditional insecticides. Interestingly, the researchers note that the engineered fungi appear to make mosquitoes sensitive to chemical insecticides again, suggesting that the two types of insect-killers might be used successfully in combination.

References:

[1] Transgenic Metarhizium rapidly kills mosquitoes in a malaria-endemic region of Burkina Faso. Lovett B, Bilgo E, Millogo SA, Ouattarra AK, Sare I, Gnambani EJ, Dabire RK, Diabate A, St Leger RJ. Science. 2019 May 31;364(6443):894-897.

[2] An entomopathogenic fungus for control of adult African malaria mosquitoes. Scholte EJ, Ng’habi K, Kihonda J, Takken W, Paaijmans K, Abdulla S, Killeen GF, Knols BG. Science. 2005 Jun 10;308(5728):1641-2.

Links:

Transgenic Fungus Rapidly Killed Malaria Mosquitoes in West African Study (University of Maryland News Release)

Malaria (National Institute of Allergy and Infectious Diseases/NIH)

Funnel-Web Spiders (Australian Museum, Sydney)

Video: 2016 Grand Challenges Spotlight Talk: Abdoulaye Diabaté (YouTube)

Raymond St. Leger (University of Maryland, College Park)

NIH Support: National Institute of Allergy and Infectious Diseases


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