Africa
This Is Why NIH Invests in Global Health Research
Posted on by Roger I. Glass, M.D., Ph.D., Fogarty International Center
Efforts over the past few years to end the COVID-19 pandemic clearly reveal how global health impacts individual wellbeing and national security. At NIH, the Fogarty International Center helps the other institutes become engaged with global health research, which investigates the dual burden of infectious disease and non-communicable disease.
Global health research also encompasses data science, economics, genetics, climate change science, and many other disciplines. For more than 50 years, Fogarty has been building partnerships among institutions in the U.S. and abroad, while training the next generation of scientists focused on universal health needs.
America’s investment in Fogarty has paid rich dividends
During the pandemic, in particular, we’ve seen researchers trained by our programs make scientific discoveries that contributed to international security. Take Jessica Manning, a former Fogarty fellow who now conducts malaria research in Phnom Penh, Cambodia. Her team at the Ministry of Health sequenced the viral strain of SARS-CoV-2, the cause of COVID-19, infecting the first Cambodian patient and documented early the spread of this novel coronavirus outside of China.
Similarly, Christian Happi, director of the African Centre of Excellence for the Genomics of Infectious Disease, Ede, Nigeria, sequenced the first SARS-CoV-2 genome in Africa. Happi was able to do it by adapting the sequencing and analytical pipelines that he’d created back when he was a Fogarty grantee studying Ebola.
In Botswana, Sikhulile Moyo leveraged the skills he’d acquired while supported by a Fogarty HIV research training grant with Max Essex, Harvard School of Public Health, Cambridge, MA, to track COVID-19 mutations for his country’s Ministry of Health. Last November, he alerted the world of a new Omicron variant. Within six weeks, Omicron became the dominant global strain, challenging the ability of COVID vaccines to control its spread. In the Dominican Republic, William Duke, a national commission member, used what he’d learned as a Fogarty trainee to help create a national COVID-19 intervention plan to prevent and control the disease.
Fogarty’s fostering of global health leaders is one way we advance scientific expertise while ensuring our nation’s biosecurity. Another is by finding effective ways to study abroad the same health conditions that affect our own population.
Research conducted in Colombia, for example, may provide clues for preventing Alzheimer’s disease in the U.S. Fogarty support brought together neuroscientists Kenneth Kosik, University of California, Santa Barbara, and Francisco Lopera, University of Antioquia, Colombia, to study members of the largest-known family with an early-onset, rapidly progressive form of the disease. Over the years, Kosik and Lopera have trained local scientists, explored gene therapy targets, investigated biomarkers to monitor disease progression, and conducted drug trials in search of a cure for Alzheimer’s.
Researchers in other fields also discover unique opportunities to investigate populations with high rates of disease. Siana Nkya, a Fogarty grantee based in Tanzania, has devoted her career to studying the genetic determinants of sickle cell disease, which affects many people around the world, including in the U.S. We hope that US-African partnerships might develop improved, affordable treatments and a cure for all patients with this devastating disease. Similarly, people in the U.S. have access to state-of-the-art HIV treatment studies in places around the globe where incidence rates are higher.
Fogarty has supported many milestone achievements in HIV research over the years. Among them is a study that took place in nine countries. The research, led by Myron Cohen of the University of North Carolina at Chapel Hill, established that antiretroviral therapy can prevent sexual transmission of HIV-1 among couples in which one person is infected and the other is not. In fact, this research informs current HIV treatment recommendations worldwide, including in the U.S.
Americans will also undoubtedly benefit from projects funded by Fogarty’s Global Brain and Nervous System Disorders Research across the Lifespan program. For example, psychologist Tatiana Balachova, University of Oklahoma, Oklahoma City, has designed an intervention for women in Russia to prevent fetal alcohol spectrum disorders. In another project in South Africa, Sandra and Joseph Jacobson, Wayne State University, Detroit, conducted the first-ever prospective longitudinal study of the syndrome. Findings from both projects are ripe for translation within an American context.
Other examples of Global Brain program investigations with broad implications in our own country include studying early psychosis in China; capacity building for schizophrenia research in Macedonia; exploring family consequences from the Zika virus in Brazil; and studying dementia and related health and social challenges in Lebanon.
These are just a few examples of Fogarty’s work and its unique mission. What is most remarkable about Fogarty is that just under 90 percent of our grants are co-funded by at least one other NIH institute, center, or office. Collaboration, both within borders and across them, is Fogarty’s formula for success.
Links:
Fogarty International Center (NIH)
Overview of Brain Disorders: Research Across the Lifespan (Fogarty)
Former Fogarty Scholar Dr Jessica Manning Helps Cambodia Respond to COVID (Fogarty)
Christian Happi: Former Fogarty Grantee Leads COVID-19 Genomics Work in Africa (Fogarty)
Sikhulile Moyo: Fogarty Fellow Recognized for Omicron Discovery (Fogarty)
William Duke: Former Fogarty HIV Trainee Helps Lead Dominican Republic’s COVID Response (Fogarty)
Kenneth Kosic and Francisco Lopera: NIH Support Spurs Alzheimer’s Research in Colombia (Fogarty)
Former Fogarty fellow Siana Nkya Tackles Sickle Cell Disease in Tanzania (Fogarty)
Tatiana Balachova: Researchers Tackle Fetal Alcohol Syndrome in Russia (Fogarty)
Sandra and Joseph Jacobson: Fetal Alcohol Exposure Research Supported by NIAAA in South Africa, Ukraine and Russia Improves Prevention, Outcomes (Fogarty)
Note: Dr. Lawrence Tabak, who performs the duties of the NIH Director, has asked the heads of NIH’s Institutes and Centers (ICs) to contribute occasional guest posts to the blog to highlight some of the interesting science that they support and conduct. This is the 22nd in the series of NIH IC guest posts that will run until a new permanent NIH director is in place.
South Africa Study Shows Power of Genomic Surveillance Amid COVID-19 Pandemic
Posted on by Dr. Francis Collins
Considerable research is underway around the world to monitor the spread of new variants of SARS-CoV-2, the coronavirus that causes COVID-19. That includes the variant B.1.351 (also known as 501Y.V2), which emerged in South Africa towards the end of 2020 [1, 2]. Public health officials in South Africa have been busy tracing the spread of this genomic variant and others across their country. And a new analysis of such data reveals that dozens of distinct coronavirus variants were already circulating in South Africa well before the appearance of B.1.351.
A study of more than 1,300 near-whole genome sequences of SARS-CoV-2, published recently in the journal Nature Medicine, shows there were in fact at least 42 SARS-CoV-2 variants spreading in South Africa within the pandemic’s first six months in that country [3]. Among them were 16 variants that had never before been described. Most of the single-letter changes carried by these variants didn’t change the virus in important ways and didn’t rise to significant frequency. But the findings come as another critical reminder of the value of genomic surveillance to track the spread of SARS-CoV-2 to identify any potentially worrisome new variants and to inform measures to get this devastating pandemic under control.
SARS-CoV-2 was first detected in South Africa on March 5, 2020, in a traveler returning from Italy. By November 2020, despite considerable efforts to slow the spread, more than 785,000 people in South Africa were infected, accounting for about half of all reported COVID-19 cases on the African continent.
Recognizing the importance of genomic surveillance, researchers led by Houriiyah Tegally and Tulio de Oliveira, University of KwaZulu-Natal, Durban, South Africa, wasted no time in producing 1,365 near-complete SARS-CoV-2 genomes by mid-September, near the end of the coronavirus’s first peak in the country. Those samples had been collected in hundreds of clinics over the course of the pandemic in eight of South Africa’s nine provinces, offering a broad picture of the spread and emergence of new variants across the country.
The data revealed three main variants, dubbed B.1.1.54, B.1.1.56, and C.1, that were responsible for 42 percent of all the infections in South Africa’s first wave. Of the 16 newly described variants, most carried single-letter changes that haven’t been identified in other countries.
The majority of changes were what scientists refer to as “synonymous,” meaning that they don’t change the structure or function of any of the virus’s essential proteins. The exception is the newly identified C.1, which includes 16 single-letter changes compared to the original sequence from Wuhan, China. One of those 16 changes swaps a single amino acid for another on SARS-CoV-2’s spike protein. That’s notable because the spike protein is a key target of antibodies and also is essential to the virus’s ability to infect human cells.
In fact, four of the most prevalent variants in South Africa all carry this same mutation. The researchers also saw three other changes that would alter the spike protein in different ways, although the significance of these for viral spread and our efforts to stop it isn’t yet clear.
Importantly, the data show that the bulk of introductions to South Africa happened early on, before lockdown and travel restrictions were implemented in late March. Subsequently, much of the spread within South Africa stemmed from hospital outbreaks. For example, an outbreak of the C.1 variant in the North West Province in April ultimately led this variant to become the most geographically widespread in South Africa by the end of August. Meanwhile, an earlier identified South African-specific variant, B.1.106, first identified in April, vanished altogether after outbreaks were controlled in KwaZulu-Natal Province, where the researchers reside.
Genomic surveillance has remarkable power for understanding the evolution of SARS-CoV-2 and tracking the dynamics of its transmission. Tegally and de Oliveira’s team notes that this type of intensive genomic surveillance now can be used on a large scale across Africa and around the world to identify new variants of SARS-CoV-2 and to develop timely measures to control the spread of the virus. They’re now working with the African CDC to expand genomic surveillance across Africa [4].
Such genomic surveillance was crucial in the subsequent identification of the B.1.351 variant in South Africa that we’ve been hearing so much about, with its potential to evade our current treatments and vaccines. By picking up on such concerning mutations early through genomic surveillance and understanding how the virus is spreading over time and space, the hope is we’ll be better informed and more adept in our efforts to get this pandemic under control.
References:
[1] Emerging SARS-CoV-2 variants. Centers for Disease Control and Prevention.
[2] Emergence and rapid spread of a new severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) lineage with multiple spike mutations in South Africa. Tegally H, Wilkinson E, Giovanetti M, Iranzadeh A, Bhiman J, Williamson C, de Oliveira T, et al. medRxiv 2020 Dec 22.
[3] Sixteen novel lineages of SARS-CoV-2 in South Africa. Tegally H, Wilkinson E, Lessells RJ, Giandhari J, Pillay S, Msomi N, Mlisana K, Bhiman JN, von Gottberg A, Walaza S, Fonseca V, Allam M, Ismail A, Glass AJ, Engelbrecht S, Van Zyl G, Preiser W, Williamson C, Petruccione F, Sigal A, Gazy I, Hardie D, Hsiao NY, Martin D, York D, Goedhals D, San EJ, Giovanetti M, Lourenço J, Alcantara LCJ, de Oliveira T. Nat Med. 2021 Feb 2.
[4] Accelerating genomics-based surveillance for COVID-19 response in Africa. Tessema SK, Inzaule SC, Christoffels A, Kebede Y, de Oliveira T, Ouma AEO, Happi CT, Nkengasong JN.Lancet Microbe. 2020 Aug 18.
Links:
COVID-19 Research (NIH)
Houriiyah Tegally (University of KwaZulu-Natal, Durban, South Africa)
Tulio de Oliveira (University of KwaZulu-Natal)
Genome Data from Africa Reveal Millions of New Variants
Posted on by Dr. Francis Collins
The first Homo sapiens emerged in Africa hundreds of thousands of years ago. We are all descended from that common pool of ancestors. Put another way, we are all Africans. While it’s not possible to study the DNA of these vanished original human populations, it is possible to study the genetic material of today’s African peoples to learn more about the human genome and its evolution over time. The degree of genetic diversity in Africa is greater than anywhere else in the world.
Progress continues to be made in this important area of genomic research. The latest step forward is a study just published in the journal Nature that analyzes more than 400 complete human genomes, including 50 distinct groups of people from 13 African countries. This work has uncovered about 3.4 million unique gene variants that had never before been described, greatly expanding our knowledge of human genetic variation and its implications for health and disease.
This work is the latest from the Human Heredity and Health in Africa (H3Africa) Initiative , which I helped establish a decade ago. This partnership between NIH, the Wellcome Trust, and the Alliance for Accelerating Excellence in Science in Africa (AESA) seeks to train a new generation of African scientists in genomic science and other disciplines, while conducting state-of-the-art health research on the African continent. The hope is to help these scientists use their new knowledge to improve human health in Africa and to help fill significant gaps in our knowledge of the diversity within human genomes.
The new study was led by Zané Lombard, the University of the Witwatersrand, South Africa; Neil Hanchard, Baylor College of Medicine, Houston; and Adebowale Adeyemo, NIH’s National Human Genome Research Institute, Bethesda, MD. It also included more than 50 other H3Africa data providers and data analysts from across Africa and around the world.
These researchers sequenced and analyzed the genomes of 426 individuals, almost all from studies and countries within the H3Africa Consortium, the network of NIH and Wellcome Trust-funded research sites in Africa. These individuals were carefully selected to provide broad coverage of the diverse landscape of African genomic variation. They also included many populations that hadn’t been studied at the genetic level before. The team focused its attention on single-letter differences, also known as single nucleotide variants (SNVs), located across the 3 billion DNA letters of the human genome.
All told, the researchers observed more than 31 million confirmed SNVs. Of the 3.4 million newly discovered SNVs, most turned up in the genomes of individuals from previously unstudied African ethnic groups with their own distinct languages. Even among SNVs that had been previously reported, several were found much more often than in other populations. That’s important because medical geneticists often include information about frequency in deciding whether a gene variant is a likely cause of rare disease. So, this more complete picture of normal genetic variation will be valuable for diagnosing such genetic conditions around the globe.
The researchers also found more than 100 regions of the genome where the pattern of genetic variation was suggestive of underlying variants that were evolutionarily favored at some time in the past. Sixty-two of those chromosomal locations weren’t previously known to be under such strong natural selection in human populations. Interestingly, those selected regions were found to contain genes associated with viral immunity, DNA repair, reproduction, and metabolism, or occurred close to variants that have been associated with conditions such as uterine fibroids and chronic kidney disease.
The findings suggest that viral infections, such as outbreaks of Ebola, yellow fever, and Lassa fever, may have played an important role over centuries in driving genetic differences on the African continent. The data also point to the possibility of human adaptation to differences across the African continent in local environments and diets, and these adaptations could be relevant to common diseases and traits we see now.
The researchers used the data to help gain insight into past migrations of human populations. The genetic data revealed complex patterns of ancestral mixing within and between groups. It also uncovered how distinct groups likely moved large distances across Africa in the past, going back hundreds to thousands of years. The findings also offered a more complete picture of the timing and extent of the migration of speakers of Africa’s most common language group (Bantu) as they moved from West Africa to the southern and eastern reaches of the continent—a defining event in the genetic history of Africa.
There’s still much more to learn about the diversity of human genomes, and a need for continued studies, including many more individuals representing more distinct groups in Africa. Indeed, H3Africa now consists of 51 projects all across the continent, focused on population-based genomic studies of many common health conditions, from heart disease to tuberculosis. As the cradle of all humanity, Africa has much to offer genomic research in the years ahead that will undoubtedly have far-reaching implications for people living in all parts of our planet.
Reference:
[1] High-depth African genomes inform human migration and health. Choudhury A et al. 2020 Oct;586(7831):741-748.
Links:
Human Heredity and Health in Africa (H3Africa) (NIH)
H3Africa (University of Cape Town, South Africa)
NIH Support: National Human Genome Research Institute; National Institute of Allergy and Infectious Diseases
Battling Malaria at the Atomic Level
Posted on by Dr. Francis Collins
Tropical medicine has its share of wily microbes. Among the most clever is the mosquito-borne protozoan Plasmodium falciparum, which is the cause of the most common—and most lethal—form of malaria. For decades, doctors have used antimalarial drugs against P. falciparum. But just when malaria appeared to be well on its way to eradication, this parasitic protozoan mutated in ways that has enabled it to resist frontline antimalarial drugs. This resistance is a major reason that malaria, one of the world’s oldest diseases, still claims the lives of about 400,000 people each year [1].
This is a situation with which I have personal experience. Thirty years ago before traveling to Nigeria, I followed directions and took chloroquine to prevent malaria. But the resistance to the drug was already widespread, and I came down with malaria anyway. Fortunately, the parasite that a mosquito delivered to me was sensitive to another drug called Fansidar, which acts through another mechanism. I was pretty sick for a few days, but recovered without lasting consequences.
While new drugs are being developed to thwart P. falciparum, some researchers are busy developing tools to predict what mutations are likely to occur next in the parasite’s genome. And that’s what is so exciting about the image above. It presents the unprecedented, 3D atomic-resolution structure of a protein made by P. falciparum that’s been a major source of its resistance: the chloroquine-resistance transporter protein, or PfCRT.
In this cropped density map, you see part of the protein’s biochemical structure. The colorized area displays the long, winding chain of amino acids within the protein as helices in shades of green, blue and gold. These helices enclose a central cavity essential for the function of the protein, whose electrostatic properties are shown here as negative (red), positive (blue), and neutral (white). All this structural information was captured using cryo-electron microscopy (cryo-EM). The technique involves flash-freezing molecules in liquid nitrogen and bombarding them with electrons to capture their images with a special camera.
This groundbreaking work, published recently in Nature, comes from an NIH-supported multidisciplinary research team, led by David Fidock, Matthias Quick, and Filippo Mancia, Columbia University Irving Medical Center, New York [2]. It marks a major feat for structural biology, because PfCRT is on the small side for standard cryo-EM and, as Mancia discovered, the protein is almost featureless.
These two strikes made Mancia and colleagues wonder at first whether they would swing and miss at their attempt to image the protein. With the help of coauthor Anthony Kossiakoff, a researcher at the University of Chicago, the team complexed PfCRT to a bulkier antibody fragment. That doubled the size of their subject, and the fragment helped to draw out PfCRT’s hidden features. One year and a lot of hard work later, they got their homerun.
PfCRT is a transport protein embedded in the surface membrane of what passes for the gut of P. falciparum. Because the gene encoding it is highly mutable, the PfCRT protein modified its structure many years ago, enabling it to pump out and render ineffective several drugs in a major class of antimalarials called 4-aminoquinolines. That includes chloroquine.
Now, with the atomic structure in hand, researchers can map the locations of existing mutations and study how they work. This information will also allow them to model which regions of the protein to be on the lookout for the next adaptive mutations. The hope is this work will help to prolong the effectiveness of today’s antimalarial drugs.
For example, the drug piperaquine, a 4-aminoquinoline agent, is now used in combination with another antimalarial. The combination has proved quite effective. But recent reports show that P. falciparum has acquired resistance to piperaquine, driven by mutations in PfCRT that are spreading rapidly across Southeast Asia [3].
Interestingly, the researchers say they have already pinpointed single mutations that could confer piperaquine resistance to parasites from South America. They’ve also located where new mutations are likely to occur to compromise the drug’s action in Africa, where most malarial infections and deaths occur. So, this atomic structure is already being put to good use.
Researchers also hope that this model will allow drug designers to make structural adjustments to old, less effective malarial drugs and perhaps restore them to their former potency. Perhaps this could even be done by modifying chloroquine, introduced in the 1940s as the first effective antimalarial. It was used worldwide but was largely shelved a few decades later due to resistance—as I experienced three decades ago.
Malaria remains a constant health threat for millions of people living in subtropical areas of the world. Wouldn’t it be great to restore chloroquine to the status of a frontline antimalarial? The drug is inexpensive, taken orally, and safe. Through the power of science, its return is no longer out of the question.
References:
[1] World malaria report 2019. World Health Organization, December 4, 2019
[2] Structure and drug resistance of the Plasmodium falciparum transporter PfCRT. Kim J, Tan YZ, Wicht KJ, Erramilli SK, Dhingra SK, Okombo J, Vendome J, Hagenah LM, Giacometti SI, Warren AL, Nosol K, Roepe PD, Potter CS, Carragher B, Kossiakoff AA, Quick M, Fidock DA, Mancia F. Nature. 2019 Dec;576(7786):315-320.
[3] Determinants of dihydroartemisinin-piperaquine treatment failure in Plasmodium falciparum malaria in Cambodia, Thailand, and Vietnam: a prospective clinical, pharmacological, and genetic study. van der Pluijm RW, Imwong M, Chau NH, Hoa NT, et. al. Lancet Infect Dis. 2019 Sep;19(9):952-961.
Links:
Malaria (National Institute of Allergy and Infectious Diseases/NIH)
Fidock Lab (Columbia University Irving Medical Center, New York)
Video: David Fidock on antimalarial drug resistance (BioMedCentral/YouTube)
Kossiakoff Lab (University of Chicago)
Mancia Lab (Columbia University Irving Medical Center)
Matthias Quick (Columbia University Irving Medical Center)
NIH Support: National Institute of Allergy and Infectious Diseases; National Institute of General Medical Sciences; National Heart, Lung, and Blood Institute
Celebrating 2019 Biomedical Breakthroughs
Posted on by Dr. Francis Collins
Happy New Year! As we say goodbye to the Teens, let’s take a look back at 2019 and some of the groundbreaking scientific discoveries that closed out this remarkable decade.
Each December, the reporters and editors at the journal Science select their breakthrough of the year, and the choice for 2019 is nothing less than spectacular: An international network of radio astronomers published the first image of a black hole, the long-theorized cosmic singularity where gravity is so strong that even light cannot escape [1]. This one resides in a galaxy 53 million light-years from Earth! (A light-year equals about 6 trillion miles.)
Though the competition was certainly stiff in 2019, the biomedical sciences were well represented among Science’s “runner-up” breakthroughs. They include three breakthroughs that have received NIH support. Let’s take a look at them:
In a first, drug treats most cases of cystic fibrosis: Last October, two international research teams reported the results from phase 3 clinical trials of the triple drug therapy Trikafta to treat cystic fibrosis (CF). Their data showed Trikafta effectively compensates for the effects of a mutation carried by about 90 percent of people born with CF. Upon reviewing these impressive data, the Food and Drug Administration (FDA) approved Trikafta, developed by Vertex Pharmaceuticals.
The approval of Trikafta was a wonderful day for me personally, having co-led the team that isolated the CF gene 30 years ago. A few years later, I wrote a song called “Dare to Dream” imagining that wonderful day when “the story of CF is history.” Though we’ve still got more work to do, we’re getting a lot closer to making that dream come true. Indeed, with the approval of Trikafta, most people with CF have for the first time ever a real chance at managing this genetic disease as a chronic condition over the course of their lives. That’s a tremendous accomplishment considering that few with CF lived beyond their teens as recently as the 1980s.
Such progress has been made possible by decades of work involving a vast number of researchers, many funded by NIH, as well as by more than two decades of visionary and collaborative efforts between the Cystic Fibrosis Foundation and Aurora Biosciences (now, Vertex) that built upon that fundamental knowledge of the responsible gene and its protein product. Not only did this innovative approach serve to accelerate the development of therapies for CF, it established a model that may inform efforts to develop therapies for other rare genetic diseases.
Hope for Ebola patients, at last: It was just six years ago that news of a major Ebola outbreak in West Africa sounded a global health emergency of the highest order. Ebola virus disease was then recognized as an untreatable, rapidly fatal illness for the majority of those who contracted it. Though international control efforts ultimately contained the spread of the virus in West Africa within about two years, over 28,600 cases had been confirmed leading to more than 11,000 deaths—marking the largest known Ebola outbreak in human history. Most recently, another major outbreak continues to wreak havoc in northeastern Democratic Republic of Congo (DRC), where violent civil unrest is greatly challenging public health control efforts.
As troubling as this news remains, 2019 brought a needed breakthrough for the millions of people living in areas susceptible to Ebola outbreaks. A randomized clinical trial in the DRC evaluated four different drugs for treating acutely infected individuals, including an antibody against the virus called mAb114, and a cocktail of anti-Ebola antibodies referred to as REGN-EB3. The trial’s preliminary data showed that about 70 percent of the patients who received either mAb114 or the REGN-EB3 antibody cocktail survived, compared with about half of those given either of the other two medicines.
So compelling were these preliminary results that the trial, co-sponsored by NIH’s National Institute of Allergy and Infectious Diseases (NIAID) and the DRC’s National Institute for Biomedical Research, was halted last August. The results were also promptly made public to help save lives and stem the latest outbreak. All Ebola patients in the DRC treatment centers now are treated with one or the other of these two options. The trial results were recently published.
The NIH-developed mAb114 antibody and the REGN-EB3 cocktail are the first therapeutics to be shown in a scientifically rigorous study to be effective at treating Ebola. This work also demonstrates that ethically sound clinical research can be conducted under difficult conditions in the midst of a disease outbreak. In fact, the halted study was named Pamoja Tulinde Maisha (PALM), which means “together save lives” in Kiswahili.
To top off the life-saving progress in 2019, the FDA just approved the first vaccine for Ebola. Called Ervebo (earlier rVSV-ZEBOV), this single-dose injectable vaccine is a non-infectious version of an animal virus that has been genetically engineered to carry a segment of a gene from the Zaire species of the Ebola virus—the virus responsible for the current DRC outbreak and the West Africa outbreak. Because the vaccine does not contain the whole Zaire virus, it can’t cause Ebola. Results from a large study in Guinea conducted by the WHO indicated that the vaccine offered substantial protection against Ebola virus disease. Ervebo, produced by Merck, has already been given to over 259,000 individuals as part of the response to the DRC outbreak. The NIH has supported numerous clinical trials of the vaccine, including an ongoing study in West Africa.
Microbes combat malnourishment: Researchers discovered a few years ago that abnormal microbial communities, or microbiomes, in the intestine appear to contribute to childhood malnutrition. An NIH-supported research team followed up on this lead with a study of kids in Bangladesh, and it published last July its groundbreaking finding: that foods formulated to repair the “gut microbiome” helped malnourished kids rebuild their health. The researchers were able to identify a network of 15 bacterial species that consistently interact in the gut microbiomes of Bangladeshi children. In this month-long study, this bacterial network helped the researchers characterize a child’s microbiome and/or its relative state of repair.
But a month isn’t long enough to determine how the new foods would help children grow and recover. The researchers are conducting a similar study that is much longer and larger. Globally, malnutrition affects an estimated 238 million children under the age 5, stunting their normal growth, compromising their health, and limiting their mental development. 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.
Measles Resurgent: The staff at Science also listed their less-encouraging 2019 Breakdowns of the Year, and unfortunately the biomedical sciences made the cut with the return of measles in the U.S. Prior to 1963, when the measles vaccine was developed, 3 to 4 million Americans were sickened by measles each year. Each year about 500 children would die from measles, and many more would suffer lifelong complications. As more people were vaccinated, the incidence of measles plummeted. By the year 2000, the disease was even declared eliminated from the U.S.
But, as more parents have chosen not to vaccinate their children, driven by the now debunked claim that vaccines are connected to autism, measles has made a very preventable comeback. Last October, the Centers for Disease Control and Prevention (CDC) reported an estimated 1,250 measles cases in the United States at that point in 2019, surpassing the total number of cases reported annually in each of the past 25 years.
The good news is those numbers can be reduced if more people get the vaccine, which has been shown repeatedly in many large and rigorous studies to be safe and effective. The CDC recommends that children should receive their first dose by 12 to 15 months of age and a second dose between the ages of 4 and 6. Older people who’ve been vaccinated or have had the measles previously should consider being re-vaccinated, especially if they live in places with low vaccination rates or will be traveling to countries where measles are endemic.
Despite this public health breakdown, 2019 closed out a memorable decade of scientific discovery. The Twenties will build on discoveries made during the Teens and bring us even closer to an era of precision medicine to improve the lives of millions of Americans. So, onward to 2020—and happy New Year!
Reference:
[1] 2019 Breakthrough of the Year. Science, December 19, 2019.
NIH Support: These breakthroughs represent the culmination of years of research involving many investigators and the support of multiple NIH institutes.
2019 Grand Challenges Annual Meeting
Posted on by Dr. Francis Collins
Study in Africa Yields New Diabetes Gene
Posted on by Dr. Francis 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
A Warm Welcome to African Fellows
Posted on by Dr. Francis Collins
A Scientist and Conservation Photographer
Posted on by Dr. Francis Collins
These stunning images of animals were taken by Susan McConnell, whose photographs have appeared in Smithsonian Magazine, National Geographic, Nature’s Best Photography, Africa Geographic, and a number of other publications. But photography is just part of her professional life. McConnell is best known as a developmental neurobiologist at Stanford University, Palo Alto, CA, and an elected member of the U.S. National Academy of Sciences.
How did McConnell find the time while tracing the development of the brain’s biocircuitry to launch a second career as a nature photographer? Her answer: Every research career has its seasons. When McConnell launched her lab in 1989 at the age of 31, she was up to her eyeballs recruiting staff, writing research grants, and pursuing many different leads in her quest to understand how neurons in the brain’s cerebral cortex are produced, differentiated, and then wired together into functional circuits.
Ebola Virus: Lessons from a Unique Survivor
Posted on by Dr. Francis Collins
Caption: Ebola virus (green) is shown on cell surface.
Credit: National Institutes of Allergy and Infectious Diseases, NIH
There are new reports of an outbreak of Ebola virus disease in the Democratic Republic of Congo. This news comes just two years after international control efforts eventually contained an Ebola outbreak in West Africa, though before control was achieved, more than 11,000 people died—the largest known Ebola outbreak in human history [1]. While considerable progress continues to be made in understanding the infection and preparing for new outbreaks, many questions remain about why some people die from Ebola and others survive.
Now, some answers are beginning to emerge thanks to a new detailed analysis of the immune responses of a unique Ebola survivor, a 34-year-old American health-care worker who was critically ill and cared for at the NIH Special Clinical Studies Unit in 2015 [2]. The NIH-led team used the patient’s blood samples, which were drawn every day, to measure the number of viral particles and monitor how his immune system reacted over the course of his Ebola infection, from early symptoms through multiple organ failures and, ultimately, his recovery.
The researchers identified unexpectedly large shifts in immune responses that preceded observable improvements in the patient’s symptoms. The researchers say that, through further study and close monitoring of such shifts, health care workers may be able to develop more effective ways to care for Ebola patients.
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