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The Infectious Disease Research Institute’s drug discovery program is finding new ways to develop TB drugs. (IDRI Photo)

To many people, tuberculosis is a disease confined to places far away or to times long gone by.

But the distance between us and this deadly pathogen is far smaller than we may imagine: in just the last six months, there have been two TB scares in the Seattle area, and one out of every three people in the world carries the TB bacteria. TB is one of the oldest and smartest known pathogens, and despite huge success in decreasing TB deaths in the past few decades, it still kills 1.5 million people every year.

“It’s co-evolved with humans throughout all of human history, and it’s done a pretty good job of it,” said Mark Orr, a senior scientist in the TB vaccine program at Seattle’s Infectious Disease Research Institute (IDRI).

Dr. David Sherman, a professor studying TB at the Center for Infectious Disease Research (CIDR) just a few blocks from IDRI, also emphasized the challenge TB poses.

“We’ve got someone dying of TB every 20 seconds somewhere in the world,” Sherman said. “It’s been pretty much at the top of the infectious killer charts for the past 200 years.”

And the treatments for TB are quickly becoming outdated and less effective, he said.

“The standard TB therapies out there, the ones they would give me if I were infected with TB, those were developed when JFK was president. They’re that old. And we desperately need new agents,” Sherman said.

Today, March 24, is World TB Day, which commemorates the discovery 135 years ago of the bacteria that causes the disease. This year’s theme is “Unite to End TB,” putting a focus on the global collaborations that are working to find cures and more effective treatments for the disease

Seattle is home to several of those collaborations. Researchers in the Emerald City and beyond have been working for decades to find more effective treatments for TB, and with the aid of these collaborations and cutting-edge technical and biological science, they are on the cusp of revolutionizing how we prevent and treat the disease.

There are two main areas TB research focuses on today: prevention, in the form of vaccines, and treatment, in the form of drug regimens.

TB drug researcher Heather Wescott in her lab at the Institute for Infectious Disease Research. (IDRI Photo / Earl Harper)

Heather Wescott is a senior scientist in the TB Drug Discovery Initiative, a public-private collaboration between IDRI, pharmaceutical giant Eli Lily and other organizations. She said there are several challenges facing researchers who seek new drugs to treat the disease.

“One is that the treatment with TB takes a very long time. Even for people that have strains that are susceptible to drugs, their treatment can last 6-9 months,” Wescott said. TB treatment also involves taking a combination of drugs, usually three or four.

“Getting people to take a complicated drug regimen for that long is difficult, and also making sure people have access to the drugs is difficult,” she said.

Increasing access to TB drugs is one of the goals of another Seattle institution, the Bill & Melinda Gates Foundation. It is working in collaboration with other organizations and researchers across the globe to make TB drugs more accessible and fuel research on ways to combat the disease.

While these collaborations are moving research on treatments forward, Wescott said the increased number of drug-resistant strains of TB is becoming another worry.

Her work at IDRI involves looking for new targets for drugs — in other words, finding parts of a TB cell that drugs can target in order to kill the disease. At the moment, many of the drugs used target the same few processes, making it more likely that the bacteria will mutate into drug-resistant forms.

Dr. David Sherman leads a lab at the Center for Infectious Disease Research that uses systems biology techniques to look for drug combinations that could combat TB. (CIDR Photo)

At CIDR, Sherman is taking a different approach to finding new drugs by using tools from systems biology.

In a nutshell, Sherman’s lab and its collaborators have developed software that can look at a drug’s effect in context. That means if a drug works by shutting off a TB cell’s way of making energy, the team can see what other changes happen in the cell as a result.

That ability is incredibly important because TB drugs are almost always used in combination with two to three other drugs. Seeing how one drug works in context means researchers can find other drugs that will work well with it.

“We could do well over a million experiments and test every one of those combinations. Except, we don’t have the time and we don’t have the money, people are dying every 20 seconds. Instead, we run this particular software, Indigo, and it predicts for us which of those combinations are going to be synergistic and which will be antagonistic,” Sherman said.

So far, his team has tested about 20 of the predictions made this way, and they have been largely accurate.

“So we still have to do the experiment, but we have to do far fewer experiments to get to combinations that could really work,” he said.

TB vaccine researcher Mark Orr in his lab at the Infectious Disease Research Institute. (IDRI Photo / Earl Harper)

On the vaccine end, different challenges emerge. Orr, the vaccine researcher, said one of the biggest ones is that we still don’t totally understand how TB interacts with our immune system, which is essential for developing an effective vaccine.

“Coming from the vaccine side, what we really need is substantially more funding to drive clinical trials,” Orr said.

There has been some promising progress on this front: in the past five years, the number of TB vaccines being studied in clinical trials has gone from just one to five. One of the vaccines currently being tested was developed at IDRI.

Sasha Larsen, an IDRI researcher who studies how TB vaccines interact with the immune system, said these trials are incredibly important, even if the vaccines themselves don’t prove effective or safe enough to use on a wide scale.

TB vaccine researcher Sarah Larsen. (Photo via Sarah Larsen)

“Having that kind of data would really inform future vaccine designs as well as strategies. So we really need more data in that realm,” Larsen said.

Orr said one of the difficulties with developing a vaccine is that TB has evolved for thousands of years to avoid the human immune system. That means many of the traditional methods of creating vaccines won’t work.

So it is a real intellectual challenge of, ‘Can we reprogram the immune system to beat that challenge, to actually eliminate the bug?’” he said.

To meet that challenge, Orr, Larsen and others on their team are studying the details of how the immune system responds to various vaccines and looking for markers that will help move us towards an effective TB vaccine.

TB deaths around the world are continuing to decrease, but that rate of decline has slowed significantly compared to the past few decades. And despite today’s promising research on new drug treatments and progress toward a TB vaccine, Sherman said there is a shadow on the horizon.

“Right now, we are at an incredible confluence of bringing big data, computers, and biological insight together to solve a problem that’s hundreds of years old, and massive. And at the same time, we’re talking about a 20-percent cut to NIH’s budget,” he said, referring to numbers in President Trump’s recent budget proposal.

“Ninety percent of the money that comes into the CIDR comes from NIH,” Sherman said. “What we’re talking about at this points is potentially is snuffing out really game-changing innovations.”

Wescott, Larson and Orr all echoed the need for continued support for TB research, among other groundbreaking research happening at NIH-funded centers in Seattle and across the country.

Life-saving results are closer than ever, and that’s no small feat when you’re talking about the deadliest pathogen in the world.

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