Research Stories

by Rebecca Howe

Tuberculosis may call to mind Old West consumptives and early 20th-century sanatoriums, yet according to the World Health Organization, the disease took the lives of more than 1.5 million people worldwide in 2006. In the United States alone, thousands of new cases are reported annually, making TB an enduring menace. The need to better understand this disease is becoming critical, note researchers at Arizona State University, especially with the emergence of antibiotic-resistant strains and increasing globalization spurring pathogen migration.

Of humans and beasts
Among those trying to decipher the origins and trajectory of Mycobacterium tuberculosis, the bacteria responsible for TB, are three ASU researchers. Graduate student Luz-Andrea "Lucha" Pfister and associate professor Anne Stone in ASU's School of Human Evolution and Social Change, and Michael Rosenberg, a Biodesign Institute researcher and assistant professor in the School of Life Sciences, are trying to establish a credible evolutionary timeline for TB.

Their research suggests that the disease migrated from humans to cattle—not the reverse, as has long been assumed. The research estimates that the evolutionary leap took place prior to the domestication of cows—more than 113,000 years ago—indicating M. tuberculosis is a much older pathogen than previously believed.

This outcome supports that of the French Pasteur Institute's Cristina Gutierrez, an evolutionary mycobacteriologist whose work first cast doubt on the cattle-to-human TB link and its date range. Gutierrez calls the findings of Pfister's team confirmation of TB's ancient origins and human-cattle transmission.

This summer, Pfister presented the results of the group's research at the annual meeting of the Society of Molecular Biology and Evolution in Barcelona, Spain. She also presented during the April assembly of the American Association of Physical Anthropologists and subsequently saw the group's research reported on in the journal Science.

Tracking a killer
With no fossil evidence to consult, studying the deep history of bacteria has only recently become possible. Genomics holds the key. Using DNA, Pfister, Stone and Rosenberg are making inroads into calibrating the watershed moments in TB's development, such as when it expanded in the human population. Through their work, they also plan to address the biogeography of the disease and what types of TB ancient people had relative to modern strains.

Why are scientists interested in TB's status thousands of years ago? Pfister puts the research into perspective: "An accurate timeframe can help us learn about the development between host and pathogen. It can aid in understanding the disease and the way it evolves, how it creates new strains to stay alive."

As Stone is quick to point out, "The data we generate can be used by clinicians to study this disease and formulate appropriate treatments. Our work is historical, but the implications are far-reaching."

One of the primary goals is to calculate a meaningful mutation rate. The established model for bacteria was developed in the 1980s in regard to E. coli, Pfister notes, "This mutation rate has been used as the universal standard, but that is not feasible. TB and E. coli are very different. Bacteria may evolve at different rates. We cannot say that one model applies to all."

Pfister, Stone and Rosenberg worked with 108 genes, compared to just over 20 genes used in the E. coli formula. As a result, they were able to delve deeper than Gutierrez at the time she conducted her ground-breaking research. "The Pasteur Institute looked at a small piece of the genome; the full genome gives a much better idea," says Stone, alluding to the team's comprehensive approach and its possibilities.

Looking at the big picture
"The work we have done so far is only one aspect of a bigger project," explains Rosenberg, who works in the Biodesign Institute's Center for Evolutionary Functional Genomics. "There are different directions we want to go with it. Of course, the main target is to get a better estimate of the rate of mycobacterium evolution, but a lot of things branch off from that."

Rosenberg, a computational evolutionary biologist who designed the program to analyze many of the sequences, says the project shows that "as we get more data and complete sequencing of full genomes, we find new ways of looking at issues, which can do away with assumptions. An example is the belief of cow-to-human transmission of TB. That was a long-held notion, but it was just an assumption."

"It is the evolutionary way of thinking that has caused us to explore this issue from new and varied angles," states Pfister. "An evolutionary perspective is also important in a contemporary sense because our species' population is growing dramatically. Soon we will reach carrying capacity. We will start producing pathogens and opportunities for problems at escalating rates."

Hope for the future
Pfister was born and raised in Chile where TB ran rampant before being subdued by aggressive government health programs. However, as in other parts of the world, Chile is presently facing a resurgence of tuberculosis. Still, Pfister is hopeful that someday the deadly pathogen will be rendered obsolete. She enthuses, "We now have lots of gene data. We can count mutations. There is so much evidence out there; we just need to link it all. If we start looking at the history and essence of TB in a holistic, transdisciplinary way, we can see the big picture and find solutions."

For more information contact Rebecca Howe, School of Human Evolution and Social Change, 480.727.6577, rebecca.howe@asu.edu