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.