It was 1999 and Eric Rubin had arrived at the Kresge Building to meet with Barry Bloom, a distinguished immunologist who would soon be appointed Dean of the School. When asked what research he’d pursue if hired as an assistant professor, Rubin said he’d like to delve into Mycobacterium avium, a model organism and distant relative of the bacterium that causes tuberculosis. “It’s an interesting disease,” Rubin reasoned. “And maybe we can learn something about TB.”
Bloom was unimpressed. “Don’t be an idiot,” he said. “Just work on TB.”
Easier said than done. Mycobacterium tuberculosis, the pathogen that causes human TB, is notoriously difficult to study and poses scientific and safety challenges at every turn. Because it’s an airborne infectious disease, researchers must don cumbersome safety gear and sequester themselves in Biosafety Level 3 containment facilities, which at the time were sparse in the Boston area. Moreover, TB grows slowly; whereas bacteria like E. coli double every 20 minutes or so, TB replicates itself only every 24 hours. A simple experiment that may take one day to run in E. coli can take three weeks in M. tuberculosis. On top of all that, Rubin had never set foot in a Biosafety Level 3 lab, nor had he envisioned devoting his career to a disease that dates back to ancient times and has for centuries outwitted scientists.
Rubin left the interview wishing for a do-over. Weeks passed, and he didn’t hear a word from Bloom. Months passed and still nothing. He was certain he’d been skipped over. Little did he know that Bloom, who had spent most of his career working on TB and knew the challenges it posed all too well, saw Rubin as a “potential superstar,” an MD and PhD who possessed the type of creative problem-solving skills that could move the field forward.
Twenty years later, much has changed. Rubin is now one of the world’s most prominent and prolific TB researchers. Trace a family tree of scientists currently studying the disease, and many of the branches eventually lead back to his lab. Last summer, Rubin was appointed chair of the Harvard T.H. Chan School Department of Immunology and Infectious Diseases (IID), and he is continuing in his role as the Irene Heinz Given Professor of Immunology and Infectious Diseases. “Eric is probably the most imaginative person in the field of tuberculosis that I know of,” Bloom says. “Not only is he full of ideas, but he gives them away like candy bars.”
Among the first big ideas Rubin pursued as a professor was a technique he jokingly dubbed TraSH—short for transposon site hybridization—which disrupted the 4,000 or so genes of M. tuberculosis to reveal those that are essential to the bacterium’s survival. “It’s MacGyver science,” says Sarah Fortune, the John LaPorte Given Professor of Immunology and Infectious Diseases and one of Rubin’s first postdocs, referring to the 1980s TV series about a secret agent/mad scientist who regularly cobbled together ingenious fixes. She adds: “The tools didn’t exist, so Eric had to build them. TraSH in particular has been transformative for TB, and many other pathogens as well. It changed our understanding of potential drug targets for the disease.”
Before TraSH, the best that drug developers could do was create as many chemicals as possible and carpet-bomb the bacteria in hopes that one of the chemicals would kill them. TraSH changed that by providing a blueprint of the bacterium’s weak links, which drugmakers could exploit.
For all of the progress represented by TraSH and other new technologies, TB remains a global scourge. It’s one of the oldest and deadliest afflictions known to humans, and was described by Hippocrates as the most common disease of his time. It has persisted through every chapter of history, killing Egyptians 5,000 years ago and thriving in the urban slums of the Industrial Revolution. The advent of antibiotics—in particular the discovery of streptomycin, the first drug proven to kill M. tuberculosis—led to a steep drop in TB cases in countries that had the resources to diagnose patients and link them with clinics and hospitals that could deliver steady access to the necessary treatments.
But in poorer countries, TB continued its deadly march forward. Drug-resistant strains emerged, and the AIDS crisis fueled a global resurgence of the disease, as latent TB infections in millions of immunocompromised patients turned into active infections. All the while, drugmakers expressed little interest in investing the huge sums of money needed to pump new TB treatments into the pipeline. A preventable disease that affects primarily the poorest patients and can be cured isn’t exactly an appealing target to build a business around, and decades of underinvestment have proven to be disastrous.
TB now kills 1.6 million people a year, more than any other infectious disease. The bacteria often nest in the deep tissue of lungs, from where they wage a slow, steady assault and spread through the body. A cough can carry the rod-shaped organism from person to person, tearing through households—husbands infecting wives, sisters infecting brothers—and killing entire families. The World Health Organization in September 2018 declared drug-resistant TB “a public health crisis and a health security threat.” Physician Jim Yong Kim, the World Bank president, has referred to extensively drug-resistant strains as “Ebola with wings.”
Empty Medicine Cabinet
Ask any TB doctor what he or she needs most, and the answer will almost certainly be: new drugs. In the past 50 years, only two have come to market, and they’re still being assessed in clinical trials. The other medications doctors have at their disposal are antibiotics that were invented in the mid-20th century and take a long time to clear an infection. A patient with drug-susceptible TB must adhere to a grueling six-month regimen. More than 85 percent of patients in this scenario will be cured. But if the patient is infected with M. tuberculosis that’s resistant to first-line drugs, treatment can take as long as two years and consist of more than 14,000 pills and months of daily injections. The drugs can cause brutal side effects, including psychosis and deafness, and fewer than half of drug-resistant TB patients who make it to the end of treatment are actually cured and do not relapse.
“If you look at HIV, there’s a huge pharmacy of medications available and new ones are added to it every year. But it’s not like that for TB. We’re constantly trying to stay ahead of drug resistance,” says KJ Seung, an infectious disease physician with the nonprofit group Partners In Health, which works to bring modern medical capabilities to the poorest regions around the world. Seung regularly treats drug-resistant TB patients in Lesotho, Peru, and North Korea. “We need more medicines,” he says.
It’s a lament that Rubin has heard countless times over his career. An MD with a specialty in infectious diseases, he’s acutely aware of the suffering TB inflicts on individuals and families around the world. Over the years, he has seen patients in Africa, Asia, and South America, mostly young people, whose drug-resistant TB has left them dying or severely debilitated. As a bench scientist, he’s intimately familiar with the challenge of developing and testing new drugs. He wants nothing more than for his laboratory to make an impact, and TraSH was a good starting point. But identifying potential targets for drugs is just one piece of a complex puzzle, and as far as Rubin is concerned, the process of generating and testing new drugs for TB desperately needs an overhaul.
“We’re still developing drugs for TB infections the same exact way we were when the first drugs for TB were developed in the 1950s,” he says. “We need to change that, and in order to change it, we need to make it easier for people to study TB and try new things, whether it be a new diagnostic or an experimental vaccine.”
“Brand New Every Time”
Twelve days after Rubin was appointed chair of IID, the 59-year-old scientist sat at his desk in an eighth-floor office, casually attired in jeans and a green polo shirt with white stripes. Not long into the conversation, Rubin had a confession to make.
“I’m going to tell you something about myself that is honest and unflattering: Why do I work on TB? The answer that I should give is that I’m a doctor, I’ve seen patients who are sick, it’s a horrible disease, and I really want to help people,” he says. “While all of that’s true, it’s not what has motivated me in the past or now. What motivates me is that doing science is really fun. It’s a blast. I wake up in the morning, I want to come to work.”
Under the microscope, M. tuberculosis is “just so weird,” Rubin says, and probing its inner workings is endlessly intriguing. “It’s not just recataloguing the same things over and over,” he says. “Everything is brand new every time.”
A quick glance around Rubin’s office conjures up an undergrad’s dorm room. There’s an old sweatshirt hanging off the handlebars of a mountain bike (on which he logs almost 30 miles a day pedaling to and from campus), a few bottles of Scotch and whiskey on a shelf, and a Presto PopLite popcorn maker still in its box. Along the windowsill is a bobblehead version of Rubin—bald, bespectacled, clad in a white lab coat—as well as bobblehead versions of Red Sox right fielder Mookie Betts and Marvelous Marvin Hagler, the Brockton, Massachusetts–born boxer who was a middleweight champion of the world and a hometown hero of Rubin’s.
“Brockton was a working-class city when I was there, a really great place to grow up,” he says. There was only one public high school, so “everyone knew everyone,” and there was none of the pretense or cutthroat competitiveness that seemed abundant in wealthier towns or private schools. “I still play cards with people that I went to kindergarten with,” he says.
Rubin was raised in a middle-class home; his mother was a school teacher who later earned a degree in library sciences, his father a salesman who never attended college. When Rubin was a young boy, his father told him that he had to go to medical school. He didn’t have to practice medicine, his father explained, but he had to at least attend medical school, the benchmark of success in the eyes of his immigrant forebears. Brainy and hardworking, Rubin easily fulfilled his father’s ambitions. He excelled academically and had his pick of the Ivy League after high school. When he was leaning toward Princeton, his father went out and purchased five Harvard T-shirts. “You can go anywhere you want,” his father said, “but you’re going to look pretty stupid at Princeton with all these Harvard shirts.”
As Rubin once told Esquire, being a good Jewish boy meant never wanting to disappoint his father, so after graduating from Harvard, he went straight into a dual MD-PhD program at Tufts. He landed in a microbiology lab studying cholera, where he first saw a side of bench science that he didn’t particularly enjoy. “There was this constant pressure of being scooped,” he says. “It turned out to be very competitive, and I didn’t like that.”
That discomfort has never left him. Keeping one’s research shrouded in secrecy until it’s published has never made much sense to Rubin. It not only inhibits problem solving and slows discovery, but it also makes doing science less fun. Over the years, Rubin has gone to great lengths to encourage collaboration across the globe.
“For years, I’ve been asking Eric questions, and reading his work, about the basic cell biology and interpretation of resistance data,” says Paul Farmer, Kolokotrones University Professor of Global Health and Social Medicine at Harvard Medical School and a leading TB expert. “A lot of folks who work on the basic science of the organism don’t pay attention to the basic science of the host—or even the basic science of the environment. I’m not talking about cellular and tissue environments—I’m talking about having patients in the mountains of rural Lesotho and having discrepant information from a clinical lab on drug susceptibility. What do you do? That’s when I’ve turned to friends like Eric, who are clinicians and who know the basic science.”
In interviews, Rubin defaults to humility and self-deprecation. When asked about his accomplishments, he says, “I’m proud of very boring things. I’m proudest of enabling people to do great experiments.” Among his peers, he’s universally regarded as a great collaborator, capable of bringing together people and ideas to advance the science. He helps organize regular meet-ups where senior and junior TB researchers from New England and New York get together to share what they’re working on, bounce ideas off one another, and polish upcoming presentations, and he’s frequently jetting off to far-flung destinations to help raise the standards of TB research and training in countries with high burdens of the disease.
“He’s willing to challenge dogma, and he’s really shaped the field of modern TB research by being a collaborative and enthusiastic leader,” says Dyann Wirth, Richard Pearson Strong Professor of Infectious Diseases.
While Rubin can be quick with a joke, “he’s very critical about science,” Wirth says, “and he wants everyone to be asking the best possible questions.”
One of the questions Rubin is keen to answer is whether it’s possible to genetically engineer a strain of M. tuberculosis that can be used to test drugs and vaccines in animals (and eventually humans). Such a strain would need several features that standard M. tuberculosis doesn’t have, including the ability to be easily detected and measured.
In a lab directly across the hall from Rubin’s office, Jeffrey Wagner, a postdoc who’s co-advised by Rubin and Fortune, places two flasks of hay-colored liquid containing harmless Mycobacterium smegmatis. “Take a whiff,” he says. One flask carried no distinct scent, aside from a faint mustiness. The other packed the olfactory wallop of a pack of wintergreen Life Savers. “What you just smelled,” Wagner explains, “is an attempt at a detection system.”
For many infectious diseases, it isn’t hard to determine how many of the causative organisms or how much of the virus is in the body. In HIV, for instance, a simple blood test can reveal how many HIV RNA copies are in the blood—what’s known as the viral load. This is critical information when it comes to developing and testing new drugs. If the viral load in a mouse infected with HIV is dropping, it’s a good indication that an experimental medication is working.
But as Wagner explains, there’s no simple way to determine how many TB organisms are in a pair of lungs, partly because the bacteria dwell deep in lung tissues. “The only way to determine bacterial load of TB is to kill the animal, grind up the lungs, spread them on an agar plate, and count the bacteria after the colonies grow up in roughly three weeks,” he says.
It’s a technical obstacle that impedes experiments and complicates drug and vaccine development. Wagner’s minty bacteria may offer a promising solution. TB is a lung infection, and lungs constantly interact with the environment via respiration. Our breath—and the breath of animals—carries all sorts of volatile markers on it, some of which smell. Under Rubin and Fortune’s guidance, Wagner has genetically engineered these bacteria to produce a volatile molecule that smells like mint. The bacteria then can be aerosolized and administered to infect an animal’s lungs. As the infection develops and the bacteria multiply, the mint-smelling “reporter molecule” can be detected and quantified using a method known as gas chromatography-mass spectrometry.
“You measure the amount of wintergreen that you smell on the breath, and that should correlate with the number of bacteria in the animal. That will tell us whether a prospective vaccine or drug is effective in reducing the bacterial load in the animals’ lungs. We’re calling the organism Mycobacterium tubercumint,” Rubin jokes.
Wordplay aside, this is the type of challenging and innovative—and fun—research that gets Rubin excited and makes him want to come to work each morning. MacGyver science at its best, it could ultimately help speed the way to new drugs and vaccines.
Reviving Infectious-Disease Research
As Rubin settles into his new role as department chair, he’s looking far beyond TB. He has concerns about the general state of infectious-disease research and worries that the field is going through a period of brain drain. “Infectious disease is so interesting and important, and it’s becoming a bit of a backwater,” he says. “We don’t attract the best and the brightest as much as we did before, both on the basic science side and on the clinical side.”
Part of the problem is that top talent is flocking to the neurosciences and oncology, where there’s ample funding and plenty of job prospects. Boston, with its booming biotech sector and world-class hospitals, is a perfect place to entice young scientists toward infectious-disease research, and Rubin is interested in forging new partnerships that better integrate the clinical side of infectious diseases with the research side.
What he wants most, though, is to change the so-far intractable global course of tuberculosis. “I’d love to complete the circle, take all the tools that we’ve made, and finally halt the disease,” Rubin says. “I’ve been at the School for 20 years, and we still don’t have anything that even looks like a drug from my lab. And I’m disappointed in that.”
Dispiriting as the pace of progress can be for Rubin, clinicians like Seung and Farmer are endlessly grateful for his singular focus. In the near term, TB is certain to remain one of the leading infectious killers. Millions will perish in the coming decades, and many millions more will become sick. But in the long term, scientists now know more than ever about the bacterium, and the discoveries made in Rubin’s lab have given new momentum to TB research.
“Basically, we got stuck for 100 years with the diagnostics, and then we got stuck 50 or 60 years with the drugs. Whenever things get stuck in clinical medicine, you can bet there’s not a lot happening on the basic science side, because that’s where discovery comes from,” says Farmer. “Eric helped fuel a renaissance. He made critical discoveries and spread the scientific riches, inspiring many other researchers along the way.”
Chris Sweeney is the senior media relations manager at the Harvard Chan School office of communications.
Photos: Kent Dayton/Harvard Chan School