With drug resistant infections on the rise, Ashlee Earl looks for clues in DNA

Nearly two centuries ago, Charles Darwin encountered a population of birds on the Galapagos Islands with remarkably varied beaks. The mandibles of “Darwin’s finches” seemed adapted to each animal’s specific diet, and the diversity of shapes and sizes of beaks that Darwin saw helped solidify his developing ideas on natural selection.

Compared to birds, however, microbes have a limited repertoire of shapes and sizes and they are largely invisible to humans. To discover the relationships between different types of bacteria, like Darwin did with the finches through observation, today’s scientists instead turn to sophisticated methods to probe microbial DNA for clues. As research scientist Ashlee Earl explained, rather than relying upon observable features, genomics approaches can uncover the molecular “clocks” within microbial genomes and reveal the evolutionary histories of these microorganisms and the roots of their remarkable diversity.

At the Broad Institute of MIT and Harvard, Earl uses genome sequencing and analysis tools to study different kinds of bacteria and understand their impact on human health, especially how bacteria evolve to resist the effects of antibiotics and how multidrug-resistant pathogens spread. As the leader of the Bacterial Genomics Group in the Genomic Center for Infectious Diseases within the Broad’s Infectious Disease and Microbiome Program, Earl hopes to help solve the growing problem of antibiotic resistant infections by identifying factors that drive resistance and monitoring for those conditions, so physicians and scientists can be prepared and intervene as threats emerge.

The rise of antibiotic-resistant pathogens is alarming and widespread. More infections are becoming harder, if not impossible, to treat as antibiotics become less effective, threatening a post-antibiotic era in which minor infections or injuries can once again kill. This grim future can be averted, Earl explained, but it will take institutional change, innovation, and discovery. “We need to continue to raise awareness that we all have a responsibility to protect the antibiotics we have now.” Existing medicines should be used judiciously in the clinic and in agriculture, and the development of new drugs will require attention, funding, and commitment from both public and private sectors.

On the research side, new technology and analysis methods are completely revolutionizing the way we think about microbes, including those that are drug-resistant. “Because of genomics, we now appreciate just how vast the number and diversity of microbes are on our planet, and how that diversity maps onto the human body in health and disease,” said Earl. “Genomics approaches have removed our reliance upon growing microbes in the lab to identify and characterize them, which is huge since we now know that we've only been able to grow a tiny fraction of microbes outside of their natural environment.”

In previous work at the Broad, Earl coordinated much of the institute’s effort to sequence the human microbiome, the collection of trillions of microbes that live on and within the human body. “By borrowing from what we’ve learned by studying the microbiome, new strategies are being developed that should help to make people resilient against resistant pathogens,” she said.

Earl and her fellow scientists study a variety of human illnesses, but their work centers on understanding the origins and spread of resistant organisms. She collaborates with local and international scientists to ask important and clinically pressing questions: How does Mycobacterium tuberculosis, the cause of TB, become resistant to antibiotics? How do the enterococci and Enterobacteriaceae, part of our normal gut microflora, evolve to become hospital-adapted, multidrug-resistant killers? And why are some women more susceptible than others to recurrent urinary tract infections, which are often treated with successive rounds of antibiotics that can lead to drug-resistant infections?

Her lab has made strides towards answering those questions. For example, the group recently reported on their efforts to track the evolution of TB resistance on a global scale. Reporting in Nature Genetics, the team discovered that resistance to isoniazid, one of the two main front-line TB drugs, most often arises before resistance to rifampicin. The result means that a common frontline TB test, which looks for rifampicin resistance only, misses many cases of mono-resistant TB; therefore, patients with isoniazid-resistant TB are being treated with drug regimens that may further encourage resistance to emerge. By examining the DNA of pathogens on a large scale, the work demonstrates how genomic insight can have immediate clinical impact.

The Broad Institute offers Earl a chance not only to do cutting-edge science, but also to work with a community of passionate, smart, and dedicated people. “As much as I love science and the thrill of discovery, it’s the people that make it fun,” she said. “I have such deep respect and admiration for our Broad team and our collaborators. Thinking about big problems and working toward solutions together is the best and most enjoyable part of my job.”

Earl’s interest in science began early. She aspired to be a scientist in second grade, but it wasn’t until her undergraduate studies at Louisiana State University (LSU) that she had more direction. “My love for microbes, in particular, was born through a chance encounter with a college guidance coach who, when I shared my desire to be a ‘genetic engineer,’ advised that I major in microbiology,” Earl remembered. “I consider this to be one of the lucky chance events of my life. I couldn’t imagine being in any other field.”

Earl went on to earn a Ph.D. in microbiology from LSU and complete postdoctoral training at Harvard Medical School with Dr. Robert Kolter, before joining the Broad in 2009. Though she is still early in her career, Earl has developed a great respect for microorganisms. “Our microbes have been a part of us and evolving with us since we became ‘we.’ We now know — and are learning more everyday — that they perform important functions that keep us well,” she said. “When they change, we change.”

Besides faster, cheaper, and better technology, if Earl could have a scientific wish fulfilled, it would be for tools, pipelines, or knowledge that would illuminate genetic dark matter. Despite advances in genetic sequencing, scientists are still extremely limited in the ability to interpret genomic data, especially regarding the function of genes. “For most predicted genes in bacteria, we have no idea what they do!” said Earl. “This is a huge challenge when trying to make sense of our results, so the ability to know the function of all bacterial genes would be incredibly enabling.”

When asked what still fascinates her about her field of study, she replied, “What doesn’t?! The more we learn about these ‘simple’ creatures, the more complexity is revealed.” In particular, she’s struck by how genomic analysis sheds light on the incredible interconnectivity among communities of microbes and how they influence each other and human health. “It’s truly fascinating. I’m both humbled and excited by the thought of how much there is still to learn.”