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To Break TB

Tuberculosis is once again the most widespread infectious-disease killer in the world. Working out of a remodeled grocery store on campus, six top-flight researchers are going after it.

By Robert Roper and Mary Ann Ayd

I knew I had a 50 percent chance of dying from the disease. The chief medical doctor at the sanatorium told me, 'Your future is behind you." ~Jacques Grosset

I knew I had a 50 percent chance of dying from the disease. The chief medical doctor at the sanatorium told me, 'Your future is behind you." ~Jacques Grosset
It’s a clear autumn day, and we’ve strolled over to one of the least likely basic science strongholds on the East Baltimore campus—a low-slung, retrofitted supermarket crouching in the shadow of the Cancer Research Building. The Frenchman we’ve come to visit is perhaps the world’s best-known tuberculosis researcher. Until just over a year ago, 73-year-old Jacques Grosset had never lived anywhere outside the French-speaking world. Then, in what is considered a spectacular coup, the Johns Hopkins Center for Tuberculosis Research lured him to Baltimore to join its group.

Now, as we sit and talk with Grosset about the disease that he has toiled for more than half a century to cure, our conversation somehow drifts to the novel 1984. More particularly it settles on the author, George Orwell, who was dying from tuberculosis as he struggled to complete the frightening tale. When Orwell succumbed to TB in 1950 at the age of 46, he became one of the last in a long line of literary artists to be felled by the disease that the 17th-century author of Pilgrim’s Progress, John Bunyan, called “the captain of all these men of death.”

Grosset says he had no idea that Orwell had tuberculosis, but when he read 1984 as a young man, something about the futuristic tale of a totalitarian world made him recognize life in a sanatorium. “I think Orwell’s illness is present in his book, in the oppressiveness of the atmosphere. You can sense the sadness of what was happening to him.”

We discover that Grosset is supremely qualified to make such an observation, because by the time he was 24 he had come face to face with tuberculosis himself. He contracted the virulent lung disease in 1953 as an intern in a French hospital and can still describe the chronic chest pain and draining fatigue. He remembers well what it was like to cough up blood daily. He had been planning to become a surgeon. Instead, he says, “the sky fell on my head.” The diagnosis was an antibiotic-resistant strain of tuberculosis that he had contracted caring for hospitalized patients. He spent the next two years in a sanatorium in the French Alps.

It’s because those years are etched in his memory that Grosset knows that the way Orwell described Big Brother was exactly the way rules used to be applied in a French TB sanatorium. Before antibiotics became available, the basis of treatment was bed rest. But for young people to stay in bed for months, he says, is virtually impossible without almost military discipline and control. “We all understood. We all tried to cheat.

“I knew I had a 50 percent chance of dying from the disease,” Grosset says. “The chief medical doctor at the sanatorium told me, ‘Your future is behind you.’”

Finally, doctors cured him by removing the top of his right lung. But the experience literally changed Grosset’s life. He would not be a surgeon. Instead, he would go on to become renowned for his studies of the disease that nearly killed him. From the sanatorium in the Alps (where he was warned to seek only part-time employment if he managed to regain enough strength to even work at all), he would travel to the Pasteur Institute in Paris. There, he would spend seven years testing new antibiotics’ ability to fight TB. He would work another seven years at the Pasteur Institute in the newly independent Algiers on ways to shorten the lengthy TB treatment time. Then he would return to Paris as a professor of microbiology at the Groupe Hospitalier Pitié-Salpetrière until, under French law, he had to retire at age 65.

But Grosset is hardly the retiring type. When the call came from Hopkins, he would jump. Because in Grosset’s field, the Johns Hopkins Center for TB Research is the most vigorous program anywhere.

****

Tuberculosis has never been off the screen at Johns Hopkins. Before the discovery of streptomycin in the 1940s, before the development of multidrug regimens and other modern strategies, TB was the most common fatal human infection. Victims of the disease were mainly the poor, but throughout history almost everybody was in danger of dying of TB. And diseases with that kind of grasp were of supreme interest to the brilliant group of scientists who began flocking to Hopkins at the end of the 19th century. Starting in 1898 with William Osler’s request for a $500 grant to study TB containment, most of the 20th-century research into both the clinical and epidemiological aspects of the disease was undertaken at or in association with the School of Medicine or the School of Public Health.

After the early 1950s, for about 30 years, tuberculosis appeared to have run its course. But by the mid-1980s, the great plague that streptomycin and other antibiotics were supposed to have eliminated had resurfaced at an alarming rate. Fueled in part by the appearance of multidrug-resistant strains, in part by the hospitable environment created by HIV infection, in part by a host of such negative social factors as homelessness and intravenous drug use, tuberculosis was once again the largest single cause of infectious death. Not only were AIDS victims dying from it in astounding numbers, people worldwide were. And while many factors can be adduced to explain this data, the central reality is that M. tuberculosis is a resourceful pathogen that swiftly takes advantage of any compromise of the immune function.

And so, in 1998, when the Johns Hopkins infectious diseases specialist Richard Chaisson brought a critical mass of brain power and funding into a remodeled grocery store at the southern end of the medical campus and began taking on the full gamut of TB’s challenges, the School of Medicine once again stepped into the vanguard of the effort to contain this scourge.

For a disease that’s entirely curable, Chaisson’s Center for Tuberculosis Research has an enormous agenda. The only effective test for latent TB is 100 years old. The vaccine still in use was developed in 1921. Diagnosis hasn’t changed since 1960. And the multidrug treatment worked out in the 1950s still takes at least six months to get rid of the infection. “Thirty years ago,” Chaisson says, “people thought everything we needed to take care of TB existed. It turns out they were wrong. The tools were good, but not good enough. We still need a better vaccine, because the existing one doesn’t work very well. And the test for latent infection—not the tine test; that’s useless—has to be refrigerated, injected just so, and interpreted several days later. We need new approaches to prevention. We need better drugs.”

Today, with grants that have grown from $3 million to more than $60 million, six principal researchers (Chaisson, Grosset, Susan Dorman, Eric Nuermberger, Yukari Manabe and William Bishai) and several collaborators at the Bloomberg School of Public Health, the center is at work on every one of these fronts. It is developing new methods for staving off TB, tests to detect and eradicate the latent infection before it progresses to clinical symptoms, and more workable treatments for the active disease. In the process, it has quietly burgeoned into an international powerhouse.

****

TB researchers, from left, Richard Chaisson, Jacques Grosset, William Bishai, and Eric Nuermberger.

TB researchers, from left, Richard Chaisson, Jacques Grosset, William Bishai, and Eric Nuermberger.

“There’s a sense of being involved in something very large,” Susan Dorman says of the work going on in the group that Chaisson built. “Something of real importance.” Dorman, an infectious diseases specialist, is the center’s testing expert. Aiming to come up with a faster and more accurate way to identify tuberculosis, she is running clinical trials in Honduras and Rio de Janeiro of a new field test, called MODS (“microscopic observation for detection and susceptibility”). Her preliminary results are good: “We can grow the TB faster,” she says, “and culture it in the presence of relevant antibiotics. It lets us know quickly which drugs a strain may be resistant to. The automated systems we have in this country are just too expensive, about $10 per sample. That just doesn’t work in sub-Saharan Africa or Asia.”

The benefits of a reduction in testing time, even by a mere week or two, could be profound. Nowadays, the standard exam in most of the developing world is still a sputum smear, which picks up only the most infectious patients. “When you factor in that you’re not getting to anything like 100 percent of all ill people,” Dorman says, “and that you’re not identifying all the ones you do get to, a diagnostic that works faster and better can mean something staggering in terms of human lives saved.”

This work to curb TB both locally and in developing nations thousands of miles from campus is one reason why Chaisson has begun referring to the center as TB’s Mall of America. “There are a number of places that have big lab programs, but nothing clinical,” he says. “Others have clinical programs but no laboratory. We cover the entire TB spectrum: very basic science, clinical research, training, clinical care—and we do it all over the globe.”

“We’re also a one-stop shop,” molecular biologist Bishai points out. “If you want to do a clinical trial, Chaisson has got sites in South Africa, South America, the Far East, the Caribbean. If you want to do a local trial, we have all the patients in Baltimore who have tuberculosis. If you want to test a new drug in an animal model, we’ve got the world’s expert, Jacques Grosset. And if you want to do some bench research on making a better vaccine or a better drug, you’ve got our lab.”

Bishai himself is a basic scientist. He investigates TB genetics and the remarkable ability of the tuberculosis bacillus to remain dormant for years. His work on the animal model for TB has proved crucial in developing treatment-shortening regimens, drugs for multidrug-resistant TB, and simplified preventive treatment for latent tuberculosis. And his genomic evaluations of M. tuberculosis are helping identify potential gene targets for new drug development, while shedding light on basic TB pathogenesis.

“We still don’t understand how people get TB, not really,” Bishai says. “It’s an airborne disease that doesn’t respect national boundaries, and it’s not something you can avoid getting with clear-cut health practices. Some people are highly susceptible. Others are resistant despite massive exposure. We’re not even sure if you can get TB a second time, after having once been cured.” Furthermore, not every antibiotic can penetrate the candlewax-like coating that encases the organism or survive the onslaught of enzymes it secretes. Standard antibiotics like penicillin are useless.

That particular impediment, Grosset says, is one of the biggest problems in curing the disease, “so every time a new antibiotic comes along, I test it.” His determination has paid off more than once. About 15 years ago, he figured out how to cut the arduous treatment regimen for latent TB, which is treated differently than the active disease (even many internists find this confusing, Chaisson says).

Typically, patients take only one drug, isoniazid, to wipe out the latent infection, but they must stay on it for a laborious nine months. Grosset discovered that by treating latent TB with a combined dose of the drugs rifampin and pyrazinamide, he could reduce the treatment time by an amazing seven months. Chaisson proved him right in clinical trials. Then, in subsequent studies, Chaisson found unacceptable rates of toxicity in the approach. And so, the group kept looking. Now, it is focused on rifapentine, a cousin of rifampin. Again, Grosset and Bishai have proven the drug works in mice to treat latent TB. So, the center is testing it in the United States, Brazil and South Africa. Keeping up with such field trials keeps Chaisson on the run for weeks at a time and in the air for thousands of miles each year.

****

Until a few years ago, TB was more of a sideline for Richard Chaisson. He arrived at Hopkins in 1988 to direct the AIDS service. Chaisson had always been fascinated by infectious diseases, though, even in 1982, when he earned his M.D. at the University of Massachusetts and almost no one shared his enthusiasm for what he calls the classic battle of man versus microbe. “In those days,” says the professor of medicine, epidemiology and international health, “infectious diseases was a dying field, mostly limited to hospital-acquired infection.”

Just a year earlier, however, the U.S. Centers for Disease Control and Prevention had described the first cases of HIV infection, and during his residency at the University of California at San Francisco , Chaisson began noticing that more and more patients were being seen by both the AIDS division and the tuberculosis clinic. Like others during those early years of AIDS, he started realizing that the two diseases—one ancient, the other brand new—seemed to overlap. In 1986, during his fellowship, he was among the first to show that the phenomenon was no coincidence. “We expected to find maybe five patients with both diseases,” he says of his study in San Francisco. “We found dozens.”

Today, Chaisson knows exactly what those early statistics meant. “HIV-positive people convert to active TB at a much increased rate, and then they infect more healthy people. A third of the world’s population,” he says, “is infected with TB and at risk of becoming sick with it. Once you’ve got TB, a vaccine won’t work. So, we’re in a race for developing more active and interventionist strategies. We need new drug-treatment models. And we need new drugs, and new methods for developing drugs, and new vaccines and methods for evaluating vaccines. Most urgently, we need bold new public health approaches to control HIV-related TB.”

“Because,” adds Bill Bishai, “TB is this incredibly sophisticated microbe with a truly scary portfolio of virulence factors.”

The treatment for active cases of TB—little changed in half a century—is an unforgiving regimen of four antibiotics (isoniazid, rifampin, pyrazinamide and either ethambutol or streptomycin) for two months, followed by two of the antibiotics for another four months. This multidrug therapy knocks out the most susceptible bugs first, then sticks around to ensure that any remaining bacteria are killed before they mutate into a resistant strain or go into hiding. Quit too soon and you’ll relapse. Drop one or more of the antibiotics and you’ll end up with bugs even more difficult to kill.

The biggest problem is getting people to stay the course. Once the symptoms of the disease disappear (after about a month of treatment), even the most motivated patients lose their incentive to keep taking their medication. Among TB’s most likely victims, the poor and those with myriad social problems, discontinuing treatment is standard behavior. When tuberculosis rates began surging in the mid-1980s, health departments in hard-hit cities like New York and Baltimore tried to lick this tendency by implementing a strategy called directly observed therapy or DOT: Health care workers were deployed to actually watch patients take their drugs. Chaisson, who’s an expert on DOT, says it’s been effective in the United States, but in other parts of the world where TB runs rampant, such labor-intensive monitoring is difficult to carry out. In Africa, even efficient DOT programs are being overwhelmed by HIV infection.

“What we see in Africa is that DOT is not sufficient,” he says. “We’re in a race for going beyond DOT, developing more epidemiologically sound—more proactive—strategies.”

Until recently, 30-year-old rifampin was the last class of drug that had panned out for active TB. Then, four years ago, both Grosset (in France) and Bishai (at Hopkins) separately launched some of the first studies on moxifloxacin, showing it to be one of the most promising new treatments ever. Since arriving at Hopkins, Grosset has continued evaluating the drug in mice. And now, Chaisson is running two big clinical trials comparing moxifloxacin with standard treatment to try to demonstrate conclusively its enormous benefits.

“Our hope,” he says, “is that it will chop off two months from treatment. Everyone in this field knows that if TB only required three months of treatment, that would be much better. It’s unlikely we’ll ever have one shot to make it go away. But six months is just not good enough.”

And so the work goes on. Grosset is convinced that one day soon there will be new tools to really control TB. “And we’re working hard to develop new treatments,” he says. “But for now, the focus is on the basic chemistry.” And despite the fact that he’s now 73—or maybe because he’s now 73—he isn’t about to quit.

“More and more, my future is behind me,” Grosset deadpans, then lets go with a booming Gallic laugh. Then, bounding from his chair to within inches of your eyes, as is his custom when he’s making a crucial point, he says, “The reason I came here is because this center is the most complete in the world. I came to Hopkins because they asked me to. I rushed to come.”

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