Battling antibiotic resistance in the lab and the clinic
Physician-scientist Roby Bhattacharyya uses genomics and his experiences treating patients to study how “superbugs” evade drugs and find better ways to combat these dangerous pathogens.
Bhattacharyya originally wanted to become a fiction writer, but during high school, his fascination with science became a stronger pull. He majored in biological chemistry at the University of Chicago and during his junior year, he had a fortuitous meeting with his academic advisor about finding a student research position that would let him dive more deeply into the molecular details of biological systems.
His advisor marched him down to the office of a new faculty member, Tobin Sosnick, who is now chair of the Department of Biochemistry and Molecular Biology at the University of Chicago. Sosnick was still unpacking boxes, yet he stopped what he was doing, sat Bhattacharyya down, and described his work to learn how proteins fold. “Right away, Tobin presented the big picture of helping to unravel a long-standing paradox in the larger scientific field, and the puzzle of protein folding really engaged me,” Bhattacharyya recalled. Sosnick welcomed Bhattacharyya into the lab as his first student researcher and worked shoulder-to-shoulder with him and another student that first year, treating his young labmates as scientific equals with an inclusive approach that would later inspire Bhattacharyya’s own research philosophy.
“Roby was great to work with, being incredibly smart and effectively functioning as a senior grad student,” said Sosnick, who fondly recalled Bhattacharyya’s unassuming demeanor. “He’d come into the lab wearing a baseball cap and carrying a tennis racket, and check out the sports scores online (maybe a little too frequently). However, he actually was one of the smartest, if not the smartest person in the room. I’m sure this combination of brains and down-to-earth demeanor benefits him today in his roles as a mentor and physician.”
TWO WHITE COATS
Bhattacharyya’s work in Sosnick’s lab solidified his interests in biology and biochemistry, but he also had a growing desire to practice medicine. As an avid tennis player during his teens, he’d had a frightening, yet ultimately benign, bout with cardiac arrhythmia. “I’d seen more than my share of doctors by the time I graduated high school, but it gave me a lot of respect for them,” he said. “I wanted to learn how the body worked in every level of detail, and to have those interactions with the patients that my physicians had had with me.”
A combined MD/PhD program offered both opportunities. In 2005, Bhattacharyya completed PhD studies at the University of California, San Francisco, in biochemistry and molecular biology, followed by two years of medical training. For his medical residency, he moved to Massachusetts General Hospital, where he was enthralled with seeing patients, especially the ones with perplexing infections.
Bhattacharyya chose to specialize in treating infections, in part because he liked the idea of caring for the entire body, rather than focusing on just one organ system. “Infectious disease is one of those relatively rare specialties in medicine where you have to understand the whole patient,” he said. “Any part of them can get infected, and you have to diagnose and manage that, no matter where it falls.” He also enjoyed connecting with patients to deduce their exposures to pathogens – their environments, their occupations, their hobbies.
After his infectious disease training at MGH and Brigham and Women’s Hospital (BWH), Bhattacharyya served as chief resident at MGH and began considering his future as a physician-scientist. He saw how genomic technology had progressed during the seven years he’d spent in medical school, spawning discoveries like new mutations underlying leukemia, and he wanted to bring the same capabilities to the study of infectious disease.
In 2012, he joined the Broad Institute as a postdoctoral researcher in the lab of Broad core institute member Deborah Hung, who is also a professor at Harvard Medical School and MGH, an infectious disease physician at BWH, and an attending critical care physician in the Medical Intensive Care Unit at BWH. Bhattacharyya continued to see patients and consult on difficult cases as an infectious disease doctor at MGH, but he spent most of his time leading research in Hung’s lab aimed at unraveling interactions between humans and their pathogens and pinpointing new targets for antimicrobial therapeutics.
In 2019, Bhattacharyya launched his own lab at the Broad, but just as his research was picking up speed, a new threat emerged that would soon overshadow his clinical, scientific, and personal life.
When Bhattacharyya first heard rumblings about the new respiratory virus spreading overseas in early 2020, his lab had only one other member, a research assistant. “Once I heard there were cases outside of China, I knew we were going to have problems, but we didn’t yet know their magnitude or pace,” said Bhattacharyya. After the lab’s first postdoctoral researcher, Alexis Jaramillo Cartagena, arrived in February, the team realized that pandemic restrictions would be coming soon. They started running experiments at a breakneck pace, gathering as much data as they could, as fast as possible, so they would have results to analyze at home during what they naively thought would be a two-week-long lab closure.
As that temporary lockdown turned into a longer pause in work, Bhattacharyya prepared to return to MGH in April for two weeks of clinical service in the infectious disease ward, and he knew COVID-19 cases would be surging by then. He frantically learned what he could about the virus and was alarmed by reports from doctors in hard-hit hospitals in Italy who were in tears, overwhelmed by seeing their colleagues becoming desperately ill. “I couldn’t fathom what it was going to be like,” he said. “At the time, we knew nothing about how to manage it.”
At MGH, Bhattacharyya typically spends six to eight weeks each year on a consult team that steps in when the primary medical team needs help with tricky infectious disease cases. But in April 2020, “suddenly, half the patients at the hospital had a brand new infection, so we were busier than ever by a long shot,” he recalled. With elective procedures on hold, parts of the hospital were eerily quiet while the intensive care unit overflowed. Bhattacharyya was particularly struck by the emptiness of ICU waiting rooms absent of grieving families, as no visitors were allowed. During that April service, he helped the medical staff create five new ICUs on the fly, while guiding care for the sickest of the sick among hundreds of critically ill patients with COVID.
At the time, he was one of the relatively few physicians who had personally cared for COVID patients. Once his two-week service was over, Bhattacharyya helped advise medical teams at his hospital and beyond on how to care for these patients, and he guided research groups in designing their COVID studies and determining the most urgent clinical questions that needed answering. He also served on a COVID task force at the Broad to advise the institute’s response to the pandemic, providing a valuable window into hospital procedures that helped guide Broad’s decision-makers.
Bhattacharyya dealt with the stress and uncertainty of the time by reading everything he could about the new virus and sharing his insights on social media and in more than a dozen town hall presentations and other events for the Broad community. The videos of his talks have been viewed and shared thousands of times online. In them, he distilled data from dozens of studies, while sharing thoughts on how he and his family were managing COVID risks, like whether he’d have his two young children wear masks on the playground.
His talks took a more hopeful tone when the COVID vaccines became a reality. “I remember the morning I got a text alert on my phone, with data showing the new vaccine’s high efficacy, and I literally started to cry. It changed everything,” he said. Bhattacharyya later helped others at MGH reach out to communities that might not trust messages about the virus and vaccines. “I felt like sharing knowledge about the vaccines was the most important thing I was doing at the time, and perhaps that I would do in my entire career.”
In 2021, the Broad gave Bhattacharyya its most prestigious award for members of the institute, in recognition of his work helping the scientific community navigate the pandemic safely. During the awards ceremony, Broad’s then-chief operating officer Jesse Souweine described the personal and professional impact he’d made. “Roby meets people where they are — scientists and nonscientists alike,” she said. “He can tackle any question, ranging from the highly specific and detailed ones about study design to the ones asked by the rest of us, like ‘Is it safe for my kids to hug their grandparents?’,” she added while fighting back tears.
Bhattacharyya and his team also contributed to COVID research, helping colleagues study how cells and tissues respond in patients with COVID and the mechanisms underlying its severity.
BACK IN THE LAB
Eventually, Bhattacharyya was able to return to the lab and resume his own scientific work, which focuses on transcriptional changes that occur when a patient is infected or when a pathogen is exposed to antimicrobial drugs. He’s since built a team of ten scientists, plus two rotating graduate students, focused on the situations that have troubled him in the clinic, such as sepsis, which afflicted far too many of Bhattacharyya’s patients. “No matter what we do, one in four patients who get sepsis will die from it, and that figure hasn’t changed in decades,” he said.
His lab is studying what happens in the immune system of patients with overwhelming systemic infection that leads to the organ failure that is so deadly in sepsis, in hopes that their findings can one day help guide medical decisions and lead to new treatments. They identified a type of white blood cell called MS1 and are studying its role in severe illness. A 2020 study that Bhattacharyya co-authored along with fellow Broad researchers Nir Hacohen, Marcia Goldberg, Michael Filbin at MGH, Paul Blainey, and Miguel Reyes found that MS1 was more abundant in the blood of patients who had bacterial urinary tract infections and who went on to develop sepsis. In healthy patients, the cells were nearly absent.
Once the pandemic hit, the team suspected that MS1 cells might play a role in viral infection, too. In severe cases of COVID, they found greater abundance and activity of MS1 cells than in healthy controls. Certain factors in the blood of severely infected patients seemed to drive the growth of these cells. They also learned that the MS1 cells strongly suppress the immune system in severe cases of COVID-19, sepsis, and many other infections. Their results suggest that key genes are expressed differently in MS1 cells from patients with sepsis compared to cells from patients who are critically ill from non-infectious causes. The findings could one day lead to a clinical test for sepsis or to therapies that manipulate MS1 cells to improve a patient’s prognosis. Bhattacharyya’s lab is continuing to explore the cell’s involvement in severe illness to inform new diagnostic and treatment approaches.
Other work in the lab involves using genomic tools to better understand how bacteria learn to dodge antimicrobial medicine, a problem that the World Health Organization deems a top global public health threat. In particular, they are studying a group of bacteria called Enterobacterales that cause pneumonia, bloodstream infections, and meningitis. These microbes often become resistant to carbapenems, a valuable group of broad-spectrum antibiotics, and occasionally they resist all other available antibiotics, making them an especially dangerous microbe.
Some of these pathogens become resistant by blocking the drug’s entry into the bacterial cell. Others secrete an enzyme that breaks down the antibiotic before it encounters the cell, and in the lab, as a colony of bacteria grows, its resistance can rapidly increase. Existing diagnostic tools for carbapenem resistance measure their ability to grow in the presence of antibiotic drugs at a single point in time, but the work of Bhattacharyya’s lab suggests that these tools may miss some cases of resistant infection if they are tested too early.
The team also worked with Broad institute scientist Ashlee Earl and her lab to analyze genetic sequences from samples of carbapenem-resistant bacteria collected from patients over a 10-year span. They identified a transcription factor that worsens carbapenem resistance, and they are currently exploring how it does so.
Another major effort in the Bhattacharyya lab aims to improve lab tests for antibiotic resistance. For most patients who are hospitalized with bacterial infections, the medical team will take a sample of blood, urine, or other bodily fluid, try to grow the bacteria from it in the lab, and then see which antibiotic will most effectively kill the microbe. This “growth-based” process takes several days, and in the meantime, patients are given broad-spectrum antibiotics, which encourage drug-resistant microbes to flourish.
As a postdoc at Broad, Bhattacharyya wondered whether there was a faster way to figure out the best antibiotic for a patient, which would reduce the use of broad-spectrum antibiotics. In 2019, he pioneered a new diagnostic approach that combines the growth-based method with measurements of gene expression in the bacteria infecting the patient. The technology, called Genotypic and Phenotypic Antibiotic Susceptibility Testing through RNA detection (GoPhAST-R), determines which antibiotics might treat a patient’s infection by first exposing bacteria from the patient to an array of antibiotics in the lab and then analyzing the bacteria’s gene expression patterns. Using a commercially available RNA-detection platform, the method looks for distinct patterns associated with drug susceptibility to identify the most effective antibiotic. GoPhAST-R generates results in a few hours, much quicker than the two to three days at best required by traditional growth-based assays.
Bhattacharyya is currently running a trial at MGH to test GoPhAST-R on patients’ blood samples as they are undergoing care, and the results look promising. He and his team are also exploring ways to develop a more portable, low-cost version that could work in lower income settings or rural clinics that might not have the same clinical lab capabilities as larger urban centers.
In addition, the team is working to apply GoPhAST-R to antibiotic susceptibility testing of tuberculosis and fungal infections. “These are illnesses in which our diagnostics are even worse than for bacteria and our therapeutic options are even more limited, but we think if these pathogens are susceptible to drugs, they'll show us transcriptionally,” Bhattacharyya said.
Having built his lab during a pandemic while continuing his clinical work, his efforts to distill and share COVID research offered him a new perspective of what’s possible in biomedical science. “It made me appreciate what research can do to inform patient care closer to real time,” Bhattacharyya said. “The fact that we had vaccines in under a year is crazy, and it has made me reflect on what a field can do with concerted effort.” He admits that antibiotic resistance may be a fundamentally larger problem than the rapid emergence of a single threatening new virus, yet he longs for the same urgency to be felt by those that conduct and fund work aimed at the resistance problem.
For Bhattacharyya, better diagnostic tools would improve patient care, but they wouldn’t replace the importance of connecting with patients on a personal level. His emphasis on personal connection is key to how he runs his research group, too. “I try to lead my lab by asking scientifically important questions in a rigorous way, but also in a kind, inclusive and supportive environment where the people in my lab are happy,” he said.
More than half the lab members are from minority groups that are underrepresented in science. “Roby goes out of his way to make science more inclusive,” said Jaramillo Cartagena, the lab’s first postdoctoral researcher. This spirit is captured in the lab’s philosophy and culture, which reads in part, “We value diversity of thought, experience, and therefore identity, and we believe that this diversity enriches the science we do, the questions we choose to ask, and the people we become.”
Bhattacharyya added, “Of course, it’s essential that people in my lab are generating data that we believe and asking questions that we think are scientifically important. All that's crucial to success. But for me, it actually starts with having people be happy. Without that, none of the rest will happen sustainably.”