Seeing the Future of African Science

This is Durban, South Africa. Aside from being a surfing mecca, a thriving center of Zulu culture, and the largest port on the African continent, Durban (located in KwaZulu-Natal province) is the global epicenter of the HIV and tuberculosis (TB) epidemics. TB is the leading cause of death amongst South Africa's HIV-infected population, which is the largest of any country in the world. And a huge proportion of South Africa's affected population resides in KwaZulu-Natal. 

I extremely fortunate to have been able to study these infections in the laboratory and the classroom as an undergraduate. But when it comes to infectious diseases, some of the hardest questions can only be answered by studying them in hard places. This was, in large part, the motivation for the founding of the KwaZulu-Natal Research Institute for Tuberculosis and HIV in Durban, and was also my motivation for moving thousands of miles away from home for two years to conduct research there. I wrote about my experience for a new magazine about science and society, called Method. Check out the excerpt below, and read the full story here. And be sure to read all of the other great content that Method has to offer. 

Between 2005 and 2006, an outbreak of extensively drug resistant tuberculosis (XDR-TB) killed all but one patient at the Church of Scotland Hospital in Tugela Ferry, South Africa. The median survival time following diagnosis was a mere 16 days, and of the patients tested, all were co-infected with HIV. The situation was desperate, the fatality rates unprecedented, and the community unprepared for an outbreak of this magnitude. Though this calamity sent shockwaves through the TB and HIV research communities, the situation was not unique. XDR-TB had been detected in all of South Africa’s nine provinces, all of its neighboring countries, and dozens of other countries across the globe. HIV was fueling the TB epidemic, and Africa was the only region of the world in which TB incidence was on the rise. No new TB drugs had been discovered in nearly 40 years. Effective vaccines against HIV or TB infection remained a dream.

More than 8,000 miles away, in Chevy Chase, Maryland, American researchers at the Howard Hughes Medical Institute (HHMI), the largest private funder of academic biomedical research in the United States, were meeting to discuss their international program. At this meeting, Dr. Bruce Walker, an HHMI investigator who leads an HIV research lab at Harvard Medical School, proposed using a model similar to what has historically worked for HHMI in the United States: investing in individual investigators who were doing great work in biomedical science.

“But,” Dr. Walker recalls, “In a place like Africa, truly transformative support would require establishment of critical infrastructure and a critical mass of investigators.”  Indeed, this meeting identified two important and intricately related problems in the developing world: the desperate need for cutting edge biomedical research, and the rarity of sites in which to conduct such research...Read more

Reprinted with permission from Method Quarterly.

Mycobacterium tuberculosis: Man’s Best Frenemy

By: Zuri Sullivan

Modern humans arose in Africa around 200,000 years ago. For an estimated 70,000 years of our history, we have co-existed with a bacterium called Mycobacterium tuberculosis (M. tb). M. tb is most notable for being the causative agent of tuberculosis (TB) disease, which kills 1.5 million people each year. However, this is only the tip of the iceberg when it comes to the ways that M. tb has influenced our biology.

We’ve developed an intimate relationship with M. tb over the last 70 millennia of our coexistence. The bacteria live inside immune cells in our lungs, and rely on us for survival. Our immune systems work to control the growth of M. tb when we become infected. If this immune response is unsuccessful, we can die from the infection.

In short, our survival and the survival of M. tb are deeply intertwined with one another, with each species attempting to subvert the other’s efforts to kill it. This arms race between a host (humans) and a pathogen (M. tb) is sometimes referred to host-pathogen co-evolution, and in the case of M. tb, it’s been going on for quite a long time.

Fighting off M. tb isn’t the only thing humans have been doing for the last 70,000 years, however. We migrated out of Africa, learned agriculture, formed nations, fought wars, made major technological advances, and fought lots of other pathogens. A history class can teach you how these and other events throughout human history have affected us as a species, as smaller populations, and as individuals. A new study published in Nature Genetics explores how major historical events have influenced our old frenemy, M. tb.

The study of human history often relies on primary sources, like ancient texts stored in archives. Unfortunately, bacteria haven’t learned to write, and scientists have only known about them for a few hundred years, so researchers studying the history of bacteria need to rely on other sources of information.  This is where deoxyribonucleic acid (DNA) comes in. You can learn more about DNA here, but the bottom line is that DNA is how information is stored in biology.

How did the researchers use this information to study the history of M. tb? When DNA is passed down from one generation to the next, small changes, or mutations, occur. It works a lot like the game of telephone, which lots of people play in elementary school. One person comes up with a silly message, and whispers it in the ear of the person next to them. That person whispers what they heard to the person next to them, and so on, until it gets back to the original message sender. The fun of the game is in seeing how much the message has changed, or mutated, as it traveled around the circle. Mutations in DNA accumulate in a similar way, but unlike the game of telephone, geneticists can quantify the changes and estimate when in history they occurred. This allowed the researchers in this study to read the DNA of M. tb like a historical text.

The team of researchers, representing 45 institutions on six continents, collected the largest assembly of a single strain of M. tb ever described: 4,987 samples from 99 countries. Using this massive collection, they traced the history of this M. tb strain over the last 6,000 years. The researchers looked at the similarities between the different bacterial samples to find out how related they were to one another. They identified seven distinct groups within the strain of M. tb, kind of like seven different families descended from one ancestor. They were able to plot the seven different groups, called clonal clusters (CC), on a geographic map because they knew exactly where each sample had come from.

Their map showed that this particular strain of M. tb had arisen in East Asia, and that certain CCs had spread to the islands of Polynesia and Micronesia, while others spread westward to Russia and Eastern Europe. The timing of this spread suggests that these CCs were likely transmitted along the Silk Road. Some CCs were present only in East Asia, the United States, and South Africa, suggesting that they were spread by immigration, rather than transmission along trade routes.

So the information in M. tb’s DNA showed how human migration has influenced the bacteria—what else can we learn from it? In addition to identifying the seven CCs of closely related bacteria, the researchers also tracked periods of overall expansion and contraction in the bacterial population. As in their first analysis, they looked at mutations in DNA. Because they occur at quantifiable rates, researchers can estimate when mutations occurred by comparing the number of observed mutations to the known mutation rate. In doing so, they generated a timeline for the expansion and contraction of this strain of M. tb.

Our close relationship with M. tb would suggest that this bacterial timeline would look a lot like the timeline of human history, and indeed, this is what the researchers found. The first major expansion in the bacterial population occurred around 200 years ago, coinciding with the Industrial Revolution. This was a time of major expansion in the human population as well, so a concomitant expansion in M. tb makes sense. The second M. tb growth spurt coincided with World War I, when people from different corners of the world were interacting with each other and likely spreading the bacteria. After this expansion, they noted a major drop in M. tb population around the 1960s, the period when the use of anti-M. tb drugs became widespread. For the first time in our history, humans had a secret weapon against the bacteria, and the findings from this study show that we were winning. Unfortunately, this downward trend was recently interrupted.  With the onset of the global HIV epidemic, the researchers observed a renewed growth in the M. tb population, reflecting the known positive influence of HIV on M. tb transmission.

 Part of the reason that we study human history is that the lessons from the actions of previous generations can inform our own decision-making. Studying bacterial history may be able to help us in a similar way. And because M. tb remains a major public health threat in many parts of the world, understanding how our actions impact its spread may help us to save the millions of lives that are affected by it.

Monsters of med school: monocyte

Monocytes are an integral part of the innate immune system. In tissues, they can differentiate into macrophages, the gluttons of the immune system. While macrophages perform a variety of functions, one of their most important roles is to eat up, or phagocytose, material around them. They eat dead cells, debris, and, importantly, infectious organisms, a process that is critical for host defense. Macrophages are also the primary infectious target of   M. tuberculosis.

Monocytes are an integral part of the innate immune system. In tissues, they can differentiate into macrophages, the gluttons of the immune system. While macrophages perform a variety of functions, one of their most important roles is to eat up, or phagocytose, material around them. They eat dead cells, debris, and, importantly, infectious organisms, a process that is critical for host defense. Macrophages are also the primary infectious target of M. tuberculosis.

Where did tuberculosis come from?

By: Zuri Sullivan

Could the ancestors of this adorable seal have been the source of tuberculosis in the Americas? A recent study published in Nature says it’s possible. A team of geneticists from institutions throughout North America, South America, and Europe, used a comparative genomics approach to try to solve the mystery of the origins of modern M. tuberculosis in the New World.

Mycobacterium tuberculosis (M. tb) is a bacterium that causes tuberculosis disease (TB).  TB is the second leading cause of infectious mortality in the world, after HIV, resulting in over 1 million deaths per year. In 2014, the global TB epidemic is largely concentrated in the developing world, but it was only about 50 years ago that the United States was battling its own TB epidemic in New York City.

In fact, the history of TB stretches back to the beginning of human history. The exact date of the origin of TB is still an active question in research, but evidence suggests that the M. tb complex (MTBC) emerged up to 70,000 years ago in Africa and has been co-evolving with humans since then. What remains a mystery, however, is how M. tb spread from the Old World (Africa, Europe, and Asia) to the New World (the Americas). Perhaps the most obvious explanation would be that European settlers brought M. tb with them when they colonized the New World. And there’s a strong precedent for this—the devastating effects of the introduction of pathogens to natives of the New World by European colonists have been an important feature of colonial history. In the case of TB, however, this explanation doesn’t hold up—Bos, et al. isolated M. tb genetic material from three ancient Peruvian skeletons that date back to approximately 1,000 years ago, long before European settlers landed in the New World, but more than 10,000 years after the land bridge across the Bering Strait had been inundated.

This finding set up an interesting conundrum: how did M. tb travel from the Old World to the New World a millennium before humans did so? To answer this question, the authors turned to a comparative genomics approach, analyzing the genomes of mycobacteria from various sources and looking at differences between them to try to determine evolutionary relationships between them. Using a next-generation sequencing technique called Illumina, they analyzed the sequences of M. tb DNA isolated from the Peruvian skeletons, as well as 259 other genomes from human and animal strains of mycobacteria. They then identified single nucleotide polymorphisms (SNPs) present in the various mycobacterial isolates. SNPs are single changes in the genetic code that arise randomly. When they confer a survival advantage to the organism they become evolutionarily selected for. The evolutionary history of a set of organisms can thus be inferred by this type of analysis. This allowed researchers to infer how closely related the different isolates were based on which SNPs they had in common.

Their results were surprising—the ancient Peruvian M. tb isolates were more closely related to animal strains of mycobacteria than to other human strains. In particular, they shared many SNPs with Mycobacterium pinnipedii, a strain of mycobacteria that infects seals and sea lions. Based on these findings, they concluded that the presence of M. tb in the New World could have come from a zoonotic (animal to human) transfer of M. pinnipedii from seals to humans living in ancient coastal communities that hunted these animals.

While it’s currently impossible to go back in time and understand how modern diseases arose, genetic approaches to studying pathogen evolution provide important clues about the history of pathogens and their co-evolution with humans. It is well-documented that ancient pathogens, like M. tb and Plasmodium (the causative agent of malaria) have played an important role in the evolution of our own immune systems. Thus, by unraveling the history of these tiny organisms, we may be able to learn more about how we evolved to fight them.