Antibiotics were once lauded for their impressive abilities to fight infection. Now, in an era of rampant antibiotic resistance, Harvard Chan researcher Yonatan Grad is pioneering new ways to track and control the spread of infectious disease — and preserve the drugs’ potency.
July 27, 2016—In any battle, ‘Know thy enemy,’ is sage advice, but those guiding words are especially relevant in the global fight against antibiotic-resistant pathogens. According to the Centers for Disease Control and Prevention (CDC), each year in the United States alone, at least 2 million people become infected with antibiotic-resistant bacteria. Some 25,000 people die as a direct result of these infections, while many more succumb to other conditions exacerbated by antibiotic resistance. In addition to this significant human toll, antibiotic resistance increases health care costs by an estimated $20 billion per year.
Understanding how microbes evolve and spread through populations and why drug-resistant infections unfold differently in different patients forms the essence of heightened efforts to combat them. The Harvard Chan School’s Yonatan Grad, MD ’01, PhD ’04, a physician-scientist working at the interface of bacterial genetics and genomics, bioinformatics, and epidemiology, is uncovering answers to these questions.
“In order to address the antibiotic-resistance crisis, we need to update public health microbiology,” says Grad, who joined the Harvard Chan School’s Department of Immunology and Infectious Diseases as an assistant professor in 2015. “That means harnessing modern genomic tools as well as computational approaches to improve how we work, both at clinical and public health levels, to lower the burden of disease and slow or contain the spread of resistance.” By bringing these diverse fields and techniques together in both the laboratory and the clinic, Grad’s work offers a fresh perspective on antibiotic resistant infections — offering ways to track and treat them better, and, at the same time, carving a path toward preserving antibiotics’ potency.
Earlier this month, Grad’s innovative approach was recognized by the Doris Duke Charitable Foundation. The organization awarded him a prestigious Clinical Scientist Development Award, which aims to support promising junior physician-scientists as they transition to independent careers.
“Yonatan is a rising star,” says Dyann Wirth, Richard Pearson Strong Professor and Chair of Immunology and Infectious Diseases at the Harvard Chan School. “Because of his creativity, productivity, collaborative abilities, and focus on critically important questions, he is poised to make important contributions to biomedicine and public health.”
Taming the ‘superbugs’
Although antibiotic resistance may seem like a new problem, Alexander Fleming, the Nobel Prize-winning scientist who discovered penicillin nearly nine decades ago, foreshadowed its rise. In a 1945 interview with the New York Times, he offered a strong warning: “The greatest possibility of evil…is the use of too-small doses, so that, instead of clearing up the infection, the microbes are educated to resist penicillin.” He added, “The thoughtless person playing with penicillin treatment is morally responsible for the death of the man who finally succumbs to infection with the penicillin-resistant organism. I hope this evil can be averted.”
Now, some seventy years after Fleming’s cautionary message, his fears have been realized on a worldwide scale. National and international public health organizations, including the CDC and the World Health Organization (WHO), have recently called for decisive steps to quell the antibiotic resistance crisis. Among the most concerning drug-resistant “superbugs”: the sexually transmitted microbe, Neisseria gonorrhoeae, which causes gonorrhea.
In the last twenty years, N. gonorrhoeae has grown increasingly drug-resistant. Now, public health officials here in the U.S. and in several countries across the globe report the emergence of resistance to third-generation cephalosporins, the antibiotic of last resort for the disease. Amidst this specter of untreatable disease, there is a critical need to identify new ways to stem the tide of resistance: In 2014, there were over 350,000 cases of gonorrhea recorded in the U.S., and the total number of infections is estimated to be more than twice that number. In a recent report from the CDC, researchers highlight a worrying trend: increasing rates of resistance to the last two available antibiotics (azithromycin and ceftriaxone) that can cure the infection. Among the N. gonorrhoeae samples studied, resistance to azithromycin shot up from 0.6 percent to 2.5 percent, while resistance to ceftriaxone rose from 0.4 percent to 0.8 percent.
One approach to this problem starts with how gonorrhea is diagnosed.
“Currently, we very rarely test the antibiotic susceptibility profile of gonococcal infections other than as part of surveillance or in cases of treatment failure,” explains Grad. “We want to treat patients when they present for care by giving them antibiotics that cure their infection. Determining the susceptibility profile is a several-day process that relies on obtaining, culturing, and testing a bacterial specimen — and requires patients to return to the clinic to receive proper treatment.”
The reasons for this approach are rooted in the realities of clinical care and public health. There are no approved rapid diagnostic tests that report which particular drugs a given strain of N. gonorrhoeae will succumb to. Therefore, current treatment guidelines recommend an empirical approach — using a one-time dose of drugs (now a combination of two different antibiotics) that, in theory, should eliminate infection in the vast majority of patients. Now, with the rise of resistance and a development pipeline for new antibiotics that has run dry, the therapeutic toolkit for gonorrhea has reached its limit.
In light of these challenges, Grad and his colleagues sought to identify ways to better control the disease and tamp down resistance. To dothis, they turned to the N. gonorrhoeae genome, decoding the genomes of bacterial isolates derived from infected patients. The work was done in close collaboration with the Gonococcal Isolate Surveillance Project (GISP), a CDC-supported effort that began in 1986 to monitor antibiotic resistance in N. gonorrhoeae nationwide and that forms the basis for the CDC’s antibiotic treatment guidelines.
In a March 2014 study published in The Lancet Infectious Diseases, Grad and his colleagues analyzed GISP data to uncover genetic differences among patient isolates that are associated with resistance to cephalosporins. Those results, together with findings from a larger study he and his colleagues recently completed that looked at two other classes of antibiotics, could help lay the foundation for the development of a rapid diagnostic test that discriminates different N. gonorrhoeae strains based on their drug resistance profiles.
Such a tool could eliminate the uncertainty that exists in current antibiotic treatment protocols. Instead of treating under the assumption that a patient is infected with the most common antibiotic-resistant strains, doctors could precisely tailor antibiotic treatment to the strains found in individual patients and perhaps even bring previously shelved antibiotics back into use.
In addition, Grad and his co-authors mined the GISP data in the 2014 Lancet study to determine how closely related different N. gonorrhoeae isolates are to each other. They linked bacterial genomics with the demographic and geographic features of infected individuals — a crucial step in identifying and characterizing transmission patterns and potential disease outbreaks. “Bacterial genomes carry a history that even the patients themselves may not know,” Grad explains. “Being able to reconstruct that history through genome sequencing can be incredibly powerful for public health systems.”
Now, as he works to extend and enhance his studies of antibiotic resistance in N. gonorrhoeae, he sees the potential for wide-ranging impact. “We can get at really big questions that have relevance not just for gonorrhea, but also for other drug-resistant infections,” he says. “If we see a highly drug-resistant strain emerge in a patient in New York or Dallas or San Francisco, for example, where is it likely to appear next? How many undetected cases are there likely to be? How can a public health system most efficiently structure its surveillance, and, ultimately, its interventions?”
At MRSA’s mercy
As Grad establishes his laboratory at the Chan School, he is applying his seemingly unquenchable curiosity to a variety of other pathogens, including respiratory syncytial virus (RSV), enterococcus, and, one of his latest pursuits, Staphylococcus aureus.
Methicillin resistant Staphylococcus aureus (MRSA) represents one of the thorniest antibiotic-resistant infections because of the microbe’s virulence and its ability to outwit many of the anti-Staphylococcus drugs in the medical arsenal. S. aureus normally lives on the skin, in the nostrils, and sometimes in the throat; most people who carry it don’t develop disease. But for individuals who carry MRSA, there is the risk of invasive infection, in which drug-resistant bacteria breach the skin barrier and invade deeper tissues, joints, bones, or even the bloodstream.
Grad’s new award from the Doris Duke Charitable Foundation will support research aimed at understanding why some people benefit from a form of MRSA control known as decolonization — which aims to remove MRSA from the body — and others do not.
“One of the things I find completely fascinating about infectious diseases is their heterogeneity,” says Grad. “Take respiratory viruses, for example. Why do some people get a cold and others end up hospitalized even when infected with the same virus? In this project on MRSA, we have an intervention that for some people is successful and for some people it’s not. We want to figure out why.”
He is teaming up with Susan Huang, MPH ’00, a professor of infectious disease at University of California Irvine, who recently completed a long-term clinical trial, known as Project CLEAR (“Changing Lives by Eradicating Antibiotic Resistance”). This randomized controlled trial compares a decolonization protocol comprising the use of antiseptic soap and mouthwash together with a topical antibiotic applied to the nostrils to the current standard of care, patient education.
Importantly, Project CLEAR is the largest and most comprehensive clinical analysis of decolonization to date. Because clinical information and MRSA samples have been collected from more than 2,000 patients at multiple time points, there is a rich source of material for biological analyses. Grad is working with collaborators at the Broad Institute and Rush University to characterize these bacterial genomes as well as their drug resistance profiles, providing insights not only into the basic biology of MRSA but also helping to improve clinical practice.
“This is a really remarkable data set,” says Grad. “In the spirit of precision medicine, we’ll have an opportunity to go beyond, ‘You’re a patient with MRSA. We’re going to try this,’ to, ‘Your Staph aureus has this profile, we think this is going to be the best approach for you.’”
Grad’s interests haven’t always centered on infectious disease, or even medicine. As an undergraduate at Johns Hopkins University, he was drawn to a variety of fields and started out studying chemistry, literature, and philosophy. While exploring people and the world around them through those mediums, he latched on to biology — specifically, the brain — and joined the laboratory of renowned neuroscientist Solomon (“Sol”) Snyder.
“I loved Sol’s group because it was full of people who were driven and excited about questions and ideas,” recalls Grad. That experience left an indelible mark, seeding a profound appreciation for intellectual community and the process of scientific discovery.
After completing his bachelor’s degree in 1996, he earned a scholarship from the Winston Churchill Foundation to spend a year at Cambridge University in England studying human genetics. He then enrolled in the MD-PhD program at Harvard Medical School, where he became increasingly convinced of the importance of computational biology. Grad joined George Church’s laboratory in the HMS Department of Genetics, where he learned computational and statistical approaches to sifting through mounds of genomic data to address key biological questions.
After finishing his PhD, Grad returned to his third-year medical clerkships, rotating among the various clinical departments in the Harvard teaching hospitals and becoming immersed in day-to-day patient care. He found himself drawn to the field of infectious diseases — as a scientific and medical discipline — in part because it weaved together many of his own personal interests.
“Infectious diseases arise through interactions between an individual and the world, so the approach to diagnosis is often based on understanding individual patients — their biology as well as their environment, behaviors, and risks — along with the biology and epidemiology of the pathogens,” says Grad.
The real clincher was that infectious disease physicians often have the power to eliminate an infection and return patients to their previous state of health. “The word ‘cure’ is not something I remember hearing much during medical school or even in residency, so when I did hear it, I was struck by its power and how it framed questions about health, illness, and medicine,” he says.
Moving forward, Grad hopes to extend his studies of antibiotic resistant infections by expanding his work on gonorrhea and MRSA, unveiling the pathogens’ biology and spread to improve clinical and public health practice.
“There’s a huge amount at stake,” says Grad. “With many fundamental questions about antibiotic resistance that remain unanswered, there’s hope that we as a research community can uncover new strategies to aid in the effort to contain or slow the spread of resistance, while also advancing new approaches to treat and prevent infectious diseases.”
Photo: Sarah Sholes