It’s a public-health nightmare in the making: Antibiotics don’t always cure infectious diseases like tuberculosis. But biologist Kim Lewis is uncovering new lines of attack. And he’s got the Gates Foundation rooting him on.
By Karen Fledscher - Illustrations by Daniel Bejar
About ten years ago, biology professor Kim Lewis had one of those “aha” moments scientists dream about. He remembers every detail.
His postdoctoral researcher at the time, Alexei Brooun, was sharing the results of a seemingly routine experiment. Included was a graph that showed how antibiotics affect a pathogen called Pseudomonas aeruginosa, which can cause fatal infections in immunosuppressed patients who have been severely burned, for example, or have cancer, AIDS, or cystic fibrosis.
“And, on the graph, it was very clear,” recalls Lewis. “There was this very, very small subpopulation [of the pathogen] that doesn’t die. And I realized, that’s probably it.”
Certain bacteria, Lewis understood with a flash, must have a unique ability to “hide” from antibiotics. This would explain why some infections seem impervious to drugs, regardless of the dosage size.
A couple of years later, Lewis and his colleagues had proved the hunch and published their first paper on the findings. It was, he says, “completely ignored.”
Several more years passed. Then, in a 2004 paper—literally at the very end of the paper, almost as an aside—Lewis suggested that “persister cells,” as he called them, may be the culprit in drug-resistant tuberculosis.
That got people’s attention. An airborne infectious disease that’s preventable and curable, TB has nevertheless become a large blip on public-health officials’ radar screens. Over the last decades, the disease has exploded across the world map, particularly in developing countries in Africa and Asia, fueled by the spread of HIV/AIDS and the emergence of drug-resistant TB strains.
Researchers and humanitarians suddenly got very interested in Lewis’s work. So interested, in fact, that last summer his lab won a high-profile $750,000 grant from the Bill and Melinda Gates Foundation, given to support promising exploratory research.
Lewis is one of eleven grantees sharing $280 million doled out by the Gates Foundation to support TB research
and speed the development of vaccines, diagnostic tests, and treatments for the killer disease. The Gates Foundation folks are hoping further study of persister cells will aid in the fight against tuberculosis.
Competition for the grant was crowded and fierce, Lewis says. “As far as I know, each and every TB research lab in the world applied.”
Even beyond that, the odds of winning an award were exceptionally thin. “Of the eleven grants, nine were designated for funding basic science, for which I competed,” says Lewis. “Six of those grants went to Seattle-based organizations, perhaps not accidentally. So then really there were three slots to compete for. One went to Europe, one went to the Midwest, and one went to the East Coast—our lab.”
What makes his award even more significant, says Lewis, is that he is the only scientist—ever—to receive a grant to study tuberculosis who had no prior involvement in TB research.
“It happened because we had a convincing hypothesis,” he says.
“They think we’re on to something.”
Pandemic Anxieties
The Gates Foundation award is a prestigious addition to Lewis’s already substantial grant-funding totals. Since arriving at Northeastern six years ago, he’s been awarded nearly $6 million in research funds, much of it coming from the National Institutes of Health.
As Lewis explains it, the Gates group “gave us a considerable amount of money for only two years, to see whether we can provide proof of principle for the basic concept we put forward.”
What is this basic concept? “That the bacteria responsible for TB form persister cells, and that this small subpopulation of dormant cells becomes extremely tolerant to all antibiotics,” Lewis says.
“We think these cells are responsible for the latency in TB,” he continues. “Which means you might seemingly get cured of the infection but—because of the persister cells hiding for decades—have a relapse ten or even twenty years later.”
In the wake of the disease’s spread, heavy-duty TB research is sorely needed.
According to the World Health Organization, nearly two billion people— a third of the world’s population—have been exposed to tuberculosis. Each year, eight million people contract the disease, and two million people die from it.
TB is most prevalent in Africa and parts of Asia. Because the disease is transmitted through coughing, sneezing, or spitting, it can wreak special havoc wherever people live in close quarters, such as urban areas.
It’s particularly deadly among the poor and those whose immune systems have been compromised by immunosuppressive drugs, substance abuse, or HIV/AIDS. A third of those infected with HIV will develop tuberculosis. It is the leading cause of death for people who have HIV.
Not everyone who has been exposed to TB develops the full-blown disease. In fact, in most exposed people, the disease stays latent and asymptomatic. But one in ten with latent infections will develop full-blown TB. Of those, more than half will die.
Tuberculosis’s recent global resurgence is the result of many factors. The growing number of HIV infections is a major contributor.
So is the neglect of TB-control programs. When TB patients start but don’t finish a course of antibiotic treatment, drug-resistant TB strains are born. Sometimes patients find it too difficult to complete a six-month course of antibiotics. In other cases, health-care workers offer improper care, or fail to provide the necessary follow-through.
The tuberculosis vaccine, almost a century old, is not very effective at shielding people from the disease. Diagnostic testing is likewise inadequate; roughly 50 percent of cases get missed.
What could happen if researchers don’t find new ways to combat TB?
“It could get pretty bad,” says Lewis. “TB is becoming one of the most potentially dangerous pathogens, because it has this exceptional ability to go into dormancy, to hide from everything we can throw at it. Then you have the highly resistant multidrug-resistant strain showing up.
“The combination of these two things makes TB enormously dangerous,” he says. “It’s only about two steps away from being a pathogen that causes a real epidemic or pandemic—and not just in Third World countries, but in Western countries with developed medicine.”
In the United States last spring, federal health officials panicked after learning that an Atlanta personal-injury lawyer diagnosed with a drug-resistant strain of TB had flown to Greece to get married, perhaps exposing other airline passengers to the risk of infection.
Once back in the States, the lawyer was held at an Atlanta hospital under armed guard for a time, then completed inpatient treatment at a Denver facility that specializes in respiratory diseases.
Internationally, groups such as the World Health Organization and Doctors Without Borders are devoting significant resources to fighting the TB battle. As of 2005, according to World Health Organization data, the per-capita incidence of TB was leveling off or falling in all areas of the globe. Unfortunately, the slight decline in incidence was being offset
by population growth, which meant
that the annual number of new cases was still rising.
“Only a truly original idea”
Lewis wasn’t troubled when his first paper on persister cells didn’t attract any attention. In fact, the resounding quiet made him happy.
He explains: “There’s this historian, Jacques Barzun, who wrote something once that stuck with me: ‘Only a truly original idea gets no response.’ So I found [the lack of response] very encouraging, actually.”
The persister-cell idea, Lewis says, “was so different, so contrary to the current wisdom of the time. People build careers on their own theories, and, suddenly, here we come. We’ve never worked in this particular field, and we say this is what we think is really going on.
“Well, in science, if one person is right, then everyone else is wrong. So it’s not easy to break through.”
Lewis hadn’t been chasing any kind of TB breakthrough at all. For years, his research had focused on E. coli, Staphylococcus aureus (staph), and Pseudomonas aeruginosa—three bacteria that, if not controlled, can cause death.
“My group pioneered research into persister cells in a number of human pathogens,” he says. “We were able to identify these cells and show they are most likely responsible for very many cases of relapsing infections, where antibiotics are mysteriously ineffective.
“You place these pathogens on a petri dish in a clinical lab,” says Lewis, “and you see they’re sensitive to antibiotics. But when you give the antibiotics to the patient, he or she doesn’t get cured. So there’s this disparity.”
When a variety of antibiotics are thrown at an infection and none of them kills it, doctors and patients face a frustrating fight.
“The mystery is what happens when you have a patient who has been having an infection for a year”—Lewis’s voice rises, to emphasize the extremity of the situation—“and the patient has been treated with many different antibiotics, and the pathogen has shown sensitivity to all the different antibiotics on a petri dish, and it’s still not working.”
He adds, “Sixty-five percent of all bacterial infections in the West have a tendency toward this relapsing, difficult-to-treat nature. That’s a lot.”
After Lewis wrote the paper on how persister cells work in E. coli, which included the speculation that similar cells may exist in tuberculosis, he got a call from the organizers of the biennial Gordon Research Conference on Tuberculosis Drug Development, inviting him to give a talk on what he was doing.
His presentation was well received, Lewis says. As a result, when he applied for the Gates grant, he did so with some confidence, knowing the TB-research community was aware of—and interested in—his work.
“One of the biggest challenges in TB drug development is understanding how the disease can persist in the body for such long periods of time,” says Ken Duncan, senior program officer at the Bill and Melinda Gates Foundation. “Dr. Lewis’s project could shed light on this critical question, and help lead to a new generation of more-powerful, faster-acting TB drugs.”
Newsmaking discoveries
The very notion of persister cells, which behave differently from seemingly identical cells, was initially considered somewhat radical in the molecular biology field. Lewis says that’s because it was “defying a really basic understanding of how genetics work.”
Think about it: When a scientist grows a large population of bacteria cells from a single cell, it would be logical to assume that all the cells—which are genetically identical—will behave in the same way.
“But suddenly,” says Lewis, “you discover that a small part of that population is very different from the bulk.” And “they are not mutants—we’ve shown and published that.”
It leads to a fascinating riddle, he says: “How come some of the twins are different from the others?”
Apparently, certain genes in the small subpopulation of persister cells turn on, as though a switch has been flipped, and send the cell into dormancy. “There’s no rhyme or reason for it,” says Lewis. “Then the question is, What are these genes that turn on?”
Lewis’s lab has already identified genes that are responsible for dormancy in E. coli. “So that gives us a clue as to how to find a similar thing in TB,” he says.
The next step: Finding out what makes the genes send the dormancy signal, which could lead to the development of drugs to prevent that from happening.
“It gives us targets to attack” is how Lewis puts it.
His research is by no means limited to work on persister cells. At least two other projects—the design of a polymer that can create a sterile surface, and the development, with fellow Northeastern biologist Slava Epstein, of a method to grow previously unculturable bacteria—have received considerable attention from the press and the scientific community.
The latter issue addresses the puzzle of unculturable bacteria, which Lewis calls “probably the biggest unsolved problem in microbiology. Maybe in biology in general.”
“Only about one percent of bacteria from the environment will grow on a petri dish,” he explains. “It’s been a big mystery for about a hundred years. These bacteria represent the majority of all species on the planet. And if we can’t grow them in the lab, we can’t study them properly.”
In 2002, Lewis and Epstein published a paper in Science describing a method they developed that grows unculturable bacteria in a new device called a diffusion chamber. The chamber allowed growth-sustaining materials from the organisms’ natural environment to diffuse freely, but restricted the movement of the cells. “An exceptionally simple device,” Lewis says. “That was our first big breakthrough.”
Since then, Lewis and Epstein have figured out a way to grow previously unculturable bacteria on regular petri dishes. In other words, says Lewis, “we learned how to domesticate them. And since we can domesticate them, they can become a source for new antibiotics.”
Most antibiotics, Lewis says, come from soil microorganisms. Yet, over the past forty years, only two new classes of antibiotics have come to the market, because of the difficulties in getting the necessary microorganisms to grow in the lab.
A company Lewis and Epstein helped found, NovoBiotic Pharmaceuticals—originally set up to license the diffusion-chamber technology—is currently trying to develop new antibiotics.
Harry Keegan III, BA’64, the CEO of Braintree Laboratories, is a NovoBiotic investor. A member of Northeastern’s corporation, board of overseers, and the College of Business Administration’s board of visitors, Keegan also served as a mentor for the company’s start-up. He calls Lewis’s science “fantastic.”
“Kim and Slava are both brilliant,” he says, “and Northeastern is beyond fortunate to have them. Their research is going to make a major impact on antibiotic development in the future.”
Lewis says that, even though they’ve worked out the “how,” he and Epstein are still pursuing a fuller understanding of why previously unculturable bacteria need such special coddling to grow in the lab.
“It seems they’ll grow if they know their neighbors—other organisms—are present,” he says. “They look for growth-promoting signals, sort of like hormones, from these neighbors. They don’t like to grow alone. Rather, they like to grow in a familiar environment to which they are adapted.”
Another headline-grabbing innovation came in 2005, when Lewis and MIT chemistry and bioengineering professor Alexander Klibanov developed a bacteria-resistant coating for surfaces.
The beauty of the coating is that it kills bacteria on contact. Imagine the uses: Hospital surfaces. Catheters, heart valves, and other medical devices. Bandages.
And much more: Subway-car poles. Restroom door handles. Banisters in stairwells. All the public surfaces that become bacteria havens because so many people touch them.
A flexible place to be
Lewis learned the ropes of molecular microbiology at Moscow State University, where he earned his doctorate in biochemistry in 1980. Seven years later, he came to the United States to teach.
Before joining Northeastern, he held faculty positions at Tufts, the University of Maryland, and MIT.
During the half-dozen years he’s been at Northeastern, Lewis has set up his own research lab, the one-and-a-half-year-old Antimicrobial Discovery Center. It’s a busy place on the third floor of the Mugar Life Sciences Building, crammed with chemicals, test tubes, high-tech equipment, and more than a dozen hardworking postdocs and graduate students.
Northeastern is the best place he’s ever worked, Lewis says—by far. “I love it at Northeastern. It’s flexible. You can get things done. We’ve had exceptionally good luck here, and I think it’s not an accident.”
He stops and corrects himself—good luck doesn’t bring success, he says. The key is feeling supported when you pursue out-of-the-box research.
“When you feel comfortable in your environment,” says Lewis, “you start taking risks you would not have taken if you were stressed. Like making persisters into a major research program when, initially, I had no funding and people were ignoring my publications. Or starting the new project with Slava Epstein on unculturable bacteria—again, with no initial funding.”
Does he expect to have another groundbreaking “aha” moment someday, like the one that led to his understanding of persister cells?
He answers simply, without hesitation.
“Yes.”
Karen Feldscher is a senior writer.