Microbiologist Brianna Manning is working to find new methods of treating Mycobacterium tuberculosis infection. She explains why phages could be a solution, and who inspires her to keep striving for answers.
My work revolves around one of the world’s deadliest pathogens – Mycobacterium tuberculosis (M. tb). I am currently an NIH Postbaccalaureate Research Education Program (PREP) scholar in the Department of Microbiology and Immunology at Albert Einstein College of Medicine in New York. Although the presence of M. tb is relatively low here in the United States, it is still a huge problem in developing countries. Around one-third of the world population is infected with the bacterium and about 2 million people die of tuberculosis each year. With the number of antibiotic-resistant variants like MDR-TB and XDR-TB dramatically increasing, we need to use other methods of treatment. Our lab is studying the genetic manipulation of M. tb and mycobacteriophages to develop vaccines and diagnostic and therapeutic tools.
Phage therapy is one thing that has been successful in cases involving multidrug-resistant pathogens. One of its many advantages is that it is harmless to humans because of a narrow host range – that is, the phage can only be hosted by specific bacteria. There are, however, some limitations that inhibit the effectiveness of phage therapy, such as the inability to target intracellular compartments. Our pathogen of interest, M. tb, is an intracellular pathogen that can be found lying metabolically inert in membrane-bound organelles (called phagosomes) within macrophages in pulmonary alveoli. To overcome this limitation, my project is to engineer a mycobacteriophage (TM4) that will incorporate a ligand, such as mannose-6-phosphate, for intracellular delivery in macrophages. This engineered phage will display green fluorescent protein (GFP) or luciferase reporter gene to assess the infectivity in intracellular M. tb. My project will serve as a step towards effectively diagnosing and treating patients with these engineered phages, and therefore poses the possibility of dramatically decreasing the spread and mortality of tuberculosis.
My father is the one who inspires me to keep striving in my work. Ten years before I was born, he was diagnosed with fibromyalgia, a neuromuscular condition where patients experience daily chronic pain. Seeing my father suffer in pain every single day is the norm to me. Unfortunately, there is no cure for fibromyalgia and in the early years of his diagnosis, his condition was poorly understood. These circumstances created a stigma for patients and their families – for example, many physicians assumed my father was faking his pain and abusing oxycodone. I hated that his condition was not believed and that I could not personally do anything about it. In recent years, clinical research has generated a better understanding of fibromyalgia, reducing the stigma and allowing insight into the condition. This made me realize that research is an extraordinary tool that seeks to explore the unknown and find answers. I knew I wanted to do the same in infectious diseases by learning how to tackle the unknown questions and improve the wellbeing of those infected with these pathogens.
Q: What kind of mindset do you need to achieve the Next Great Impossible?
A: My mindset is understanding that failures happen. You should take failures as opportunities to learn and create successes. I recently experienced a failure with a project concerned with creating a phage that can detect sterilization conditions. I found out by whole-genome sequencing that the phage, which I’d been working on for a long time, had the wrong promoter. This finding set me back months of progress as it invalidated all the assays I’d done. But I learned to be open-minded and that these situations can happen. With that in mind, I realized I had to be resilient and move forward.