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Clare Smith examines role of genetics in tuberculosis infection

By Megan Bard

UMass Medical School Communications

December 11, 2017

The Women in Science video series on UMassMedNow highlights the many areas of research conducted by women at UMass Medical School.

For Clare M. Smith, PhD, the questions, not the answers, are the most exciting and challenging aspect of research. To be sure, she has a lot of questions.

“Science is one of those few jobs where you can combine innovation and creativity,” said Dr. Smith, a postdoc in the Sassetti lab who earned her PhD in medical research from the Menzies Research Institute at the University of Tasmania, Australia. “It takes all kinds of people and all kinds of skills to ask the big questions. You don’t know what the answer will be, and maybe necessarily you won’t find it, but being able to ask those big questions is why I love this job.”

Smith’s passion for genomic research, specifically infectious disease and the interaction between the host and pathogen, led to her current position studying the genetic basis for susceptibility to the bacterium Mycobacterium tuberculosis.

“Infectious diseases are really interesting to study; malaria and TB, these are old diseases, but still very much misunderstood and affect millions of people every year. Why are there people who are susceptible to diseases like malaria and TB and why are others not? Does the answer lie in our own genomes?” she said.

As a student in Australia, Smith used a unique approach in her study of malaria. She focused on the genetics of the human host, not of the parasite, in trying to determine why the pathogen was so persistent and difficult to eradicate. Her research identified a specific enzyme in the human red blood cell that the parasite needs for survival; the discovery could change how malaria is treated.

The desire to approach an old question from a different perspective and understand the crosstalk between the pathogen and host genomes is what attracted her to the lab of Christopher M. Sassetti, PhD, professor of microbiology & physiological systems, which she joined as postdoc in 2013.

“Chris Sassetti has pioneered many tools for understanding bacterial genetics. It’s exciting to be in the Sassetti lab, learning new bacterial approaches but also bringing my own host genetics experience. It’s through the collaboration of many researchers with different ideas and approaches that we can truly tackle this age-old scourge that is TB,” she said.

One-third of the world's population is infected with tuberculosis, making it one of the world’s most deadly diseases. In 2015, 10.4 million people became sick with TB and 1.8 million died from TB-related illness, according to the Centers for Disease Control and Prevention. Antibiotic treatment of TB is long and expensive. In addition, scientists have warned of significant drug resistance.

“This is a global health problem and just one reason to keep studying the disease,” said Smith, who was recently awarded a Charles King Postdoctoral Fellowship and a grant from the Broad Institute to continue her research.

According to Smith, infection with the bacterium results in a spectrum of disease. A small number of people are infected and immediately highly susceptible. The majority of people, however, are able to mount an immune response that walls off the TB bacteria inhaled into the lungs. In fact, most people don’t even know they have TB; one in three people are latently infected and don’t show symptoms. However, at some point, reactivation can occur, in which the bacteria escape our surveillance system and start growing again.

“So you have these three distinct hallmarks of the disease. Are you susceptible? Resistant? Will you reactivate later? We think there is a genetic basis to this. Can we use what we know about the host and bacterial genomes to create new drugs or understand why are those people susceptible?” she said.

The Sassetti lab has developed an animal model system to study the host and bacterial genetics in combination that will allow scientists to learn more about why the current vaccine doesn’t universally protect and to identify the types of immune responses the new vaccines should target. Specifically, they’ve created an assay to look at the host and pathogen genomes to understand how well BCG, the vaccine that more than half the world’s human population receives, works and why it only works in some people.

“Similar to people, several of the animal models are highly protected by BCG, but some aren’t at all. Genetics could play a big part in who are non-responders. If we can get the model responding to the new vaccines, we’ll be more confident that we can protect these previously unprotectable people,” she said.

While her focus is on the host, Smith said the pathogen is not neglected.

“What is it about the pathogen genome that is adapting to all of our unique genomes? Really, it’s this age-old battle of two genomes being played out,” she said.

Understanding how a pathogen interacts with the human genome is an interesting science question and one with global health relevance, she said.

“Pathogens have co-evolved with us and have had a large hand in shaping our genomes. In the case of both malaria and TB, along with many other infectious diseases, learning about how the pathogen has adapted to our own genomes may pave the way for new understanding and new therapeutic approaches,” Smith said.

Women in Science videos:
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Katherine Fitzgerald focuses on novel discoveries in innate immunity
Molly Waring focused on helping mothers manage their weight
Shlomit Schaal develops methods for early detection of diabetic retinopathy
Jill Zitzewitz is unraveling protein misfolding to understand disease
PhD Candidate Yvonne Chan a ‘protein engineer’