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Celebrating 2019 Biomedical Breakthroughs

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Science 2019 Biomedical Breakthroughs and a Breakdown

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.


Exploring the Universality of Human Song

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Analysis of Music-Internationally

It’s often said that music is a universal language. But is it really universal? Some argue that humans are just too culturally complex and their music is far too varied to expect any foundational similarity. Yet some NIH-funded researchers recently decided to take on the challenge, using the tools of computational social science to analyze recordings of human songs and other types of data gathered from more than 300 societies around the globe.

In a study published in the journal Science [1], the researchers conclude that music is indeed universal. Their analyses showed that all of the cultures studied used song in four similar behavioral contexts: dance, love, healing, and infant care. What’s more, no matter where in the world one goes, songs used in each of those ways were found to share certain musical features, including tone, pitch, and rhythm.

As exciting as the new findings may be for those who love music (like me), the implications may extend far beyond music itself. The work may help to shed new light on the complexities of the human brain, as well as inform efforts to enhance the role of music in improving human health. The healing power of music is a major focus of the NIH-supported Sound Health Initiative.

Samuel Mehr, a researcher at Harvard University, Cambridge, MA, led this latest study, funded in part by an NIH Director’s Early Independence Award. His multi-disciplinary team included anthropologists Manvir Singh, Harvard, and Luke Glowacki, Penn State University, State College; computational linguist Timothy O’Donnell, McGill University, Montreal, Canada; and political scientists Dean Knox, Princeton University, Princeton, NJ, and Christopher Lucas, Washington University, St. Louis.

In work published last year [2], Mehr’s team found that untrained listeners in 60 countries could on average discern the human behavior associated with culturally unfamiliar musical forms. These behaviors included dancing, soothing a baby, seeking to heal illness, or expressing love to another person.

In the latest study, the team took these initial insights and applied them more broadly to the universality of music. They started with the basic question: Do all human societies make music?

To find the answer, the team accessed Yale University’s Human Relations Area Files, an internationally recognized database for cultural anthropologists. This rich resource contains high-quality data for 319 mostly tribal societies across the planet, allowing the researchers to search archival information for mentions of music. Their search pulled up music tags for 309 societies. Digging deeper in other historical records not in the database, the team confirmed that the remaining six societies did indeed make music.

The researchers propose that these 319 societies provide a representative cross section of humanity. They thus conclude that it is statistically probable that music is in fact found in all human societies.

What exactly is so universal about music? To begin answering this complex question, the researchers tapped into more than a century of musicology to build a vast, multi-faceted database that they call the Natural History of Song (NHS).

Drawing from the NHS database, the researchers focused on nearly 5,000 vocally performed songs from 60 carefully selected human societies on all continents. By statistically analyzing those musical descriptions, they found that the behaviors associated with songs vary along three dimensions, which the researchers refer to as formality, arousal, and religiosity.

When the researchers mapped the four types of songs from their earlier study—love, dance, lullaby, and healing—onto these dimensions, they found that songs used in similar behavioral contexts around the world clustered together. For instance, across human societies, dance songs tend to appear in more formal contexts with large numbers of people. They also tend to be upbeat and energetic and don’t usually appear as part of religious ceremonies. In contrast, love songs tend to be more informal and less energetic.

Interestingly, the team also replicated its previous study in a citizen-science experiment with nearly 30,000 participants living in over 100 countries worldwide. They found again that listeners could tell what kinds of songs they were listening to, even when those songs came from faraway places. They went on to show that certain acoustic features of songs, like tempo, melody, and pitch, help to predict a song’s primary behavioral function across societies.

In many musical styles, melodies are composed of a fixed set of distinct tones organized around a tonal center (sometimes called the “tonic,” it’s the “do” in “do-re-mi”). For instance, the researchers explain, the tonal center of “Row Your Boat” is found in each “row” as well as the last “merrily,” and the final “dream.”

Their analyses show that songs with such basic tonal melodies are widespread and perhaps even universal. This suggests that tonality could be a means to delve even deeper into the natural history of world music and other associated behaviors, such as play, mourning, and fighting.

While some aspects of music may be universal, others are quite diverse. That’s particularly true within societies, where people may express different psychological states in song to capture their views of their culture. In fact, Mehr’s team found that the musical variation within a typical society is six times greater for that reason than the musical diversity across societies.

Following up on this work, Mehr’s team is now recruiting families with young infants for a study to understand how they respond to their varied collection of songs. Meanwhile, through the Sound Health Initiative, other research teams around the country are exploring many other ways in which listening to and creating music may influence and improve our health. As a scientist and amateur musician, I couldn’t be more excited to take part in this exceptional time of discovery at the intersection of health, neuroscience, and music.

References:

[1] Universality and diversity in human song. Mehr SA, Singh M, Knox D, Ketter DM, Pickens-Jones D, Atwood S, Lucas C, Jacoby N, Egner AA, Hopkins EJ, Howard RM, Hartshorne JK, Jennings MV, Simson J, Bainbridge CM, Pinker S, O’Donnell TJ, Krasnow MM, Glowacki L. Science. 2019 Nov 22;366(6468).

[2] Form and function in human song. Mehr SA, Singh M, York H, Glowacki L, Krasnow MM. Curr Biol. 2018 Feb 5;28(3):356-368.e5.

Links:

Sound Health Initiative (NIH)

Video: Music and the Mind—A Q & A with Renée Fleming & Francis Collins (YouTube)

The Music Lab (Harvard University, Cambridge, MA)

Samuel Mehr (Harvard)

NIH Director’s Early Independence Award (Common Fund)

NIH Support: Common Fund


Charting Research Careers in Global Health

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That’s me at the 67th annual meeting of the American Society of Tropical Medicine and Hygiene (ASTMH). I took part in a townhall-style conversation with ASTMH President Chandy John (far middle, blue shirt). We discussed global health and NIH’s efforts to build career opportunities for trainees abroad. Afterwards, folks in the audience gathered with follow-up questions and to ask for selfies with me, which is always fun. The session was held on November 22, 2019 at the Gaylord National Resort and Convention Center, Washington, D.C. Credit: Karen Goraleski.

Uncovering a Hidden Zika Outbreak in Cuba

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Zika Virus in Cuba
Credit: Sharon Isern, steampunkphage.com.

When Brazilian health officials discovered four years ago that the mosquito-borne Zika virus could cause severe birth defects and other serious health problems, it prompted a major effort across the Americas to curb the infection by controlling mosquitoes and issuing travel advisories. By mid-2017, the hard work seemed to have paid off, and reports of new Zika infections had nearly stopped.

But it turns out Zika may be tougher to control than once thought. New research shows that a large, previously hidden outbreak of Zika virus disease occurred in Cuba, just when it looked like the worst of the epidemic was over. The finding suggests that the Zika virus can linger over long periods, and that mosquito control efforts alone may slow, but not necessarily stop, the march of this potentially devastating infectious disease.

When combating global epidemics, it’s critical to track the spread of dangerous viruses from one place to the next. But some viruses can be tougher to monitor than others, and that certainly has been the case with Zika in the Americas. Though the virus can harm unborn children, many people infected with Zika never feel lousy enough to go to the doctor. Those who do often have symptoms that overlap with other prevalent tropical diseases, such as dengue and chikungunya fever, making it hard to recognize Zika.

That’s why in Brazil, where Zika arrived in the Americas by early 2014, this unexpected viral intruder went undetected for well over a year. By then, it had spread unnoticed to Honduras, circulating rapidly to other Central American nations and Mexico—likely by late 2014 and into 2015.

In the United States, even with close monitoring, a small local outbreak of Zika virus in Florida also went undetected for about three months in 2016 [1]. Then, in 2017, Florida officials began noticing something strange: new cases of Zika infection in people who had traveled to Cuba.

This came as a real surprise because Cuba, unlike most other Caribbean islands, was thought to have avoided an outbreak. What’s more, by then the Zika epidemic in the Americas had slowed to a trickle, prompting the World Health Organization to delist it as a global public health emergency of international concern.

Given the Cuban observation, some wondered whether the Zika epidemic in the Americas was really over. Among them was an NIH-supported research team, including Nathan Grubaugh, Yale School of Public Health, New Haven, CT; Sharon Isern and Scott Michael, Florida Gulf Coast University, Fort Myers; and Kristian Andersen, The Scripps Research Institute, La Jolla, CA, who worked closely with the Florida Department of Health, including Andrea Morrison.

As published in Cell, the team was able to document a previously unreported outbreak in Cuba after the epidemic had seemingly ended [2]. Interestingly, another research group in Spain also recently made a similar observation about Zika in Cuba [3].

In the Cell paper, the researchers show that between June 2017 and October 2018, all but two of 155 cases—a whopping 98 percent of travel-associated Zika infections—traced back to Cuba. Further analysis suggests that the outbreak in Cuba was likely of similar magnitude to outbreaks that occurred in other Caribbean nations.

Their estimates suggest there were likely many thousands of Zika cases in Cuba, and more than 5,000 likely should have been diagnosed and reported in 2017. The only difference was the timing. The Cuban outbreak of Zika virus occurred about a year after infections subsided elsewhere in the Caribbean.

To fill in more of the blanks, the researchers relied on Zika virus genomes from nine infected Florida travelers who returned from Cuba in 2017 and 2018. The sequencing data support multiple introductions of Zika virus to Cuba from other Caribbean islands in the summer of 2016.

The outbreak peaked about a year after the virus made its way to Cuba, similar to what happened in other places. But the Cuban outbreak was likely delayed by a year thanks to an effective mosquito control campaign by local authorities, following detection of the Brazilian outbreak. While information is lacking, including whether Zika infections had caused birth defects, it’s likely those efforts were relaxed once the emergency appeared to be over elsewhere in the Caribbean, and the virus took hold.

The findings serve as yet another reminder that the Zika virus—first identified in the Zika Forest in Uganda in 1947 and for many years considered a mostly inconsequential virus [4]—has by no means been eliminated. Indeed, such unrecognized and delayed outbreaks of Zika raise the risk of travelers innocently spreading the virus to other parts of the world.

The encouraging news is that, with travel surveillance data and genomic tools —enabled by open science—it is now possible to detect such outbreaks. By combining resources and data, it will be possible to develop even more effective and responsive surveillance frameworks to pick up on emerging health threats in the future.

In the meantime, work continues to develop a vaccine for the Zika virus, with more than a dozen clinical trials underway that pursue a variety of vaccination strategies. With the Zika pandemic resolved in the Americas, these studies can be harder to conduct, since proof of efficacy is not possible without active infections. But, as this paper shows, we must remain ready for future outbreaks of this unique and formidable virus.

References:

[1] Genomic epidemiology reveals multiple introductions of Zika virus into the United States. Grubaugh et al. Nature. 2017 Jun 15;546(7658):401-405.

[2] Travel surveillance and genomics uncover a hidden Zika outbreak during the waning epidemic. Grubaugh ND, Saraf S, Gangavarapu K, Watts A, Tan AL, Oidtman RJ, Magnani DM, Watkins DI, Palacios G, Hamer DH; GeoSentinel Surveillance Network, Gardner LM, Perkins TA, Baele G, Khan K, Morrison A, Isern S, Michael SF, Andersen .KG, et. al. Cell. 2019 Aug 22;178(5):1057-1071.e11.

[3] Mirroring the Zika epidemics in Cuba: The view from a European imported diseases clinic. Almuedo-Riera A, Rodriguez-Valero N, Camprubí D, Losada Galván I, Zamora-Martinez C, Pousibet-Puerto J, Subirà C, Martinez MJ, Pinazo MJ, Muñoz J. Travel Med Infect Dis. 2019 Jul – Aug;30:125-127.

[4] Pandemic Zika: A Formidable Challenge to Medicine and Public Health. Morens DM, Fauci AS. J Infect Dis. 2017 Dec 16;216(suppl_10):S857-S859.

Links:

Video: Uncovering Hidden Zika Outbreaks (Florida Gulf Coast University, Fort Myers)

Zika Virus (National Institute of Allergy and Infectious Diseases/NIH)

Zika Virus Vaccines (NIAID)

Zika Free Florida (Florida Department of Health, Tallahassee)

Grubaugh Lab (Yale School of Public Health, New Haven, CT)

Andersen Lab (The Scripps Research Institute, La Jolla, CA)

NIH Support: National Institute of Allergy and Infectious Diseases; National Center for Advancing Translational Sciences


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


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