Figure 1 ~ Bacteria infecting your body continue to evolve as they reproduce. [Image credit: CDC/ Judith Noble-Wang, Ph.D.]

             Like most of the trillions of bacteria that surround us, growing on doorknobs or floating in the breeze, Burkholderia dolosa poses no risk to healthy people. Yet in the mid-1990’s, an outbreak of B. dolosa killed half of the thirty-nine cystic fibrosis patients at a single Boston hospital [1]. How did that bacterium evolve from a harmless resident of onion skins into a virulent infection of the lung, and how can we protect our most vulnerable from the next attack?

            In a recent Nature Genetics paper [2], a team of scientists based at the Kishony lab at Harvard Medical School tried to answer this question by studying the pattern of mutations in the bacteria’s genes. They reconstructed the history of the battle between the body and invader, and are now using that information to design new antibiotic treatments.

            Cystic fibrosis is an inherited disorder which causes thick mucus to form in the airways, made lethal when that mucus becomes a bacterial breeding ground. Each day a patient is infected, the billions of bacteria in their lung will divide a half-dozen times. Every time a bacterium divides, it needs to make a new copy of its entire million-letter long genome. A single copying mistake could create a new mutation that confers antibiotic resistance, so that bacterium and all of its offspring will survive the drug treatment. This potential to quickly acquire resistance makes the infection devilishly difficult to eliminate with antibiotics. A later mutation might camouflage one of those bacteria from the immune system, and another mutation might adjust the bacterium to the oyxgen-poor environment of the sick lung. Pretty soon, the descendants of these well-adapted bacteria will have replaced their less fit ancestors, making the infection even harder to treat n more tenacious with time.

            To figure out which bacterial genes had been under pressure during the Boston outbreak, the Harvard researchers sequenced the genomes of dozens of bacteria living in the phlegm of one of the survivors. The researchers reconstructed a family tree of the infection, tracing the changes which had happened since the first invading bug founded the colony. What they found surprised them.

            Traditional theories of evolution predict that a bacterium with a beneficial mutation will eventually take over the population, its offspring multiplying until the old genetic version is completely crowded out. Bacteria with different versions of a gene should coexist only temporary. Yet the scientists found seventeen genes that had mutated differently in distinct segments of the population. While even a seemingly useless mutation can win the genetic lottery and grow rich in descendants, it is rather suspicious when two of its neighbors pull off the same feat. This may be a signal that changes to those genes were extremely important during the course of the infection. If different mutations alter the function of a crucial gene in the same way, then both may be selected for–natural selection only notices the downstream effect of a mutation, not the precise place it occurs.

Figure 2 ~ Each bacterial genome (row) has many mutations (ticks). Which are important for the infection and which are random? The green hotspots, regions with mutations in many organisms, are likely to be crucial genes. [Image credit: Hannah Somhegyi.]

            That appears to be exactly what happened in a gene crucial for bacterial reproduction that is targeted by a common antibiotic. The gene produces a protein which keeps DNA from getting tangled up during replication like a mistreated yo-yo. The antibiotic captures this protein so that, when tension builds up in the DNA, bacterial reproduction grinds to a halt [3]. Sequencing revealed that this antibiotic had almost certainly been tried: absolutely no cells with the original version of the gene survived. But the B. dolosa colony had evolved two independent ways to resist the antibiotic: ninety percent of the bacteria had a mutation in a certain segment of the gene and the other ten percent had a mutation in a different segment nearby. Perhaps these subtly changed the shape of the protein, making it harder for the antibiotic to bind.

            Are the other sixteen genes with multiple independent mutations as crucial to the bacteria’s battle plans? The same research group is currently following up on a promising lead: mutations found in an oxygen-dependent pathway may have helped the bacteria move from its onion skin origin into the oxygenated human lung. Soon we may see a new antibiotic designed to disrupt that pathway.

            This group’s approach may become quite popular, as the paper’s first author, Tami Lieberman, explains, “The finding of parallelism within patients means we can identify other such genes under strong selection without the need to track infections over time. This will enable us to quickly look for such genes in other infections, including acute ones.” Until recently, performing this analysis would have taken months and costs tens of thousands of dollars. But with modern cheap sequencing technologies, the culturing and sequencing can be done in one week for a few hundred bucks. Every multiply mutated gene they find will represent a challenge faced by the bacterium living in the human body, and the researchers can design new therapies to increase those challenges.

            Tuberculosis, a lung infection which kills 1.5 million people per year, is next on the list of targets. Samples are in the mail from collaborators in South Africa.

Joshua Batson is a graduate student in the mathematics department at MIT and a curious observer of modern developments in evolutionary biology and genetics.


[1] Allen S. (2003, December 3), Children’s Hospital fights new bacteria strain. The Boston Globe.

[2] Lieberman TD et al. (2013, December), Genetic variation of a bacterial pathogen within individuals with cystic fibrosis provides a record of selective pressures. Nature Genetics 46 82-87.

[3] rdb07959 (2009) Topoisomerase 1 and 2.

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