A new discovery in the fight against tuberculosis

{***Pause/Music***}

{***Noah***}

Coming up on Harvard Chan: This Week in Health…

A new discovery in the fight against tuberculosis

{***Eric Rubin Soundbite***}

(This would be a sort of unusual drug target, one that enables other drugs to work better.)

TB infects millions of people each year—and the treatment takes several months.

In this week’s episode, we’ll explain how new research could one day open the door to much faster treatment of the disease.

{***Pause/Music***}

{***Noah***}

Hello and welcome to Harvard Chan: This Week in Health. It’s Thursday, June 15, 2017…I’m Noah Leavitt.

{***Amie***}

And I’m Amie Montemurro.

This week we’ll be focusing on tuberculosis—which is one of the top 10 causes of death worldwide.

{***Noah***}

And the statistics on the disease are staggering.

According to the WHO—in 2015 TB sickened 10.8 million people—and killed 1.8 million.

Over 95% of those deaths occurred in low- or middle-income countries.

{***Amie***}

TB mostly attacks a person’s lungs and it can be spread through the air.

The good news with TB is that it is preventable and it is curable.

{***Noah***}

But the cure is not an easy one.

People with TB have to take drugs for 6 to 9 months—which can be especially difficult in poor areas with few medical resources.

{***Amie***}

In this week’s episode, we’ll explain how scientists are working at the cellular level to understand why TB is so difficult to treat—and to find new approaches to shorten the length of treatment for patients.

{***Noah***}

I spoke with Eric Rubin, Irene Heinz Given Professor of Immunology and Infectious Diseases at the Harvard Chan School.

A study that Rubin co-authored with Hesper Rego and Rebecca Audette found that a single protein appears responsible for the ability of some tuberculosis-causing bacteria to evade antibiotics.

We’ll talk about that new finding—and its significance in a few minutes—but first I spoke with Rubin about *why TB is so difficult to treat.

He says it’s a question scientists are still working to pin down—but he offered some insight.

{***Eric Rubin Soundbite***}

Eric Rubin: It probably takes a long time to treat any infection. But acute infections– infections that occur in a few days and get better in a few days– are probably easier because once you kill 90% or 95% of the bacteria, you’re done. But TB, we don’t seem to have a very good way of getting rid of the bacteria.

Our defense mechanisms aren’t so good at getting rid of any residual bacteria. So we really have to kill them well. And what that means is that we know there’s always a residual population left after short times of treatment. We have to extend that treatment to try to kill off that last remaining population.

Noah Leavitt: When it takes six months to treat disease, are there any sort of consequences from that? Or is it just really difficult, in terms of making sure that there’s enough of the drugs necessary to treat the disease?

I think both. So the longer you take a drug, the more likely you are to have side effects of those medications. And because of those side effects, the more likely you are to stop early.

And if you stop early, then you have an increased chance of having a relapse disease. But of course, the logistics are super important. TB occurs in areas of the world that are poor.

And in those areas, it’s hard to maintain drug supplies. More than that, in order to ensure that people take their drugs, there’s a large infrastructure that has to be built. So in TB, like other diseases, if you take your drugs for a couple of weeks, you feel a lot better.

And there’s not a lot of incentive to keep on taking pills if you don’t understand why you’re taking them. So the WHO has instituted a system called Directly Observed Therapy, where every dose of, medicine which is every day, has to be seen by an observer. And in most parts of the world, that observer is a health professional, a nurse, or a health aide of some sort who’s at a clinic.

So people have to go to the clinic every single day to take their medicine for the whole course of their six months of treatment. That is really, really expensive. The drugs themselves are very cheap.

But the infrastructure that you must maintain to keep that drug supply in place, to pay all those people. And the loss of work hours for everyone who has to go to the clinic every day is enormous.

{***Noah***}

So, there’s clearly an incentive to find ways to shorten the treatment timeline for TB.

{***Amie***}

And that’s where those new findings from Rubin and his team come in.

{***Noah***}

We mentioned at the beginning that scientists aren’t exactly sure why TB is so difficult to treat.

But they have some theories.

And one focuses on the fact that individual bacteria are all different from each other—in other words there’s incredible diversity even at the cellular level.

Here’s Rubin again.

{***Eric Rubin Soundbite***}

Eric Rubin: Think about it like identical twins.

So identical twins have the same genetics. And yet, sometimes they turn out to be very different people, even when they’re raised in the same environment. There are all of these stories of twins where one attempted to murder the other twin.

One was raised as in Nazi Germany as a member of the Nazi Youth and another was raised in a Jewish home in Trinidad. So genetics doesn’t determine everything. We know that for mycobacteria.

Because if you take a culture, you take a bunch of bacteria all genetically identical– all sisters to each other– grown together in one test tube, they all look a little different from each other. So there is variation that occurs outside of genetics. We call that phenotypic variation.

And so we already know that the bacteria are different sizes. They have somewhat different growth rates. They have different shapes from each other.

And we were interested in what can we determine at the level of a single cell that we can measure that’s different.

{***Noah***}

And the bacteria that causes TB—mycobacterium tuberculosis has an even further set of unique characteristics, says Rubin.

{***Amie***}

When a cell divides it creates so-called “daughter cells.”

And in the case of mycobacterium tuberculosis, those cells are physiologically diverse, making them less susceptible to antibiotics—which means that it takes much longer for TB drugs to eliminate all of the bacteria.

{***Noah***}

But Rubin’s team was able to shed important light on the mechanism underlying the cell division that occurs.

They studied a similar bacterium—called mycobacterium smegmatis

And they found that without a specific protein product of a gene called LAMA1 the bacteria formed after cell division were far less diverse—which, according to Rubin, would also make them more uniformly susceptible antibiotics.

{***Eric Rubin Soundbite***}

Eric Rubin: Each individual bacterium is different from every other one. And each has its own susceptibility to drug treatment so that when you take with drugs, some die very quickly. And some die slowly or not at all. What we found was a mechanism that underlies that, at least for some antibiotics. And if we take away a specific protein that the cell normally uses, then they all become very similar to each other, in terms of being killed by drugs.

Noah Leavitt: So would the application down the road be that you develop a drug to target that protein?

Eric Rubin: I think that’s right. It’s a kind of unusual way approach. Because this protein isn’t necessary for the bug to survive. So if you made a drug that blocked the effect of this protein, it would do nothing.

It might do a little. But it wouldn’t do very much because the bacteria don’t need this. However, if you treat it with a second drug, then you’d kill all of the bacteria much more rapidly. So this would be a sort of unusual drug target, one that enables other drugs to work better.

{***Noah***}

Now Rubin does caution that developing a drug that affects that gene or its protein would be difficult.

{***Amie***}

And that drug alone wouldn’t be enough to treat TB.

Instead—it might be something additive—a drug given along with the usual course of antibiotics.

{***Noah***}

It would not only make the bacteria more susceptible to drugs—but they would also die much more quickly—which would be a key way to shorten the course of treatment for TB.

{***Amie***}

But there are still many unanswered questions.

For example, Rubin’s lab is now trying to figure out how fast bacteria would die if the protein is inhibited or what type of dose would be required.

{***Noah***}

Rubin adds that this is just one of many approaches for advancing TB treatment.

Because it is such a complex—and often deceptive—infection, scientists have many areas of focus.

{***Eric Rubin Soundbite***}

Eric Rubin: For example some drugs have trouble getting to certain bacteria because they just don’t penetrate into the inflamed areas where the bacteria are very well. And if we could improve drug penetration, that would help. There is a hypothesis that some bacteria go dormant.

And they’re tough to kill under those conditions. And it’s been difficult to tell whether or not that it’s important because we don’t really have a molecular handle on how to manipulate that.

Noah Leavitt: So when you say go dormant, what do you mean by that?

Eric Rubin: These bacteria stop growing or stop metabolizing at a normal rate. And perhaps those bacteria in vitro– in the laboratory– are harder to kill. So it’s possible that also occurs during infection. We just don’t know.

Noah Leavitt: It could be infecting someone, but a drug couldn’t actually find it in the person’s body?

Eric Rubin: Or the drug just got to it, and the bacteria didn’t care. So it just didn’t work. One of the mysteries of TB is something called– one of the great mysteries– is something called latency.

People get infected and in fact, the number that gets thrown around is that a third of the world– you know, 1 and 1/2 billion people– are infected with TB walking around today. They’re not sick. And more than 90% of people who get infected aren’t sick.

More than 90% will never get sick. But we know those people can get sick if they become immunocompromised later, for example. So what’s going on?

Where are the bacteria hiding out? What are they doing during that time? And I think there are conflicting stories out there as to whether or not they’re actually growing like normal bacteria do. Or they’re not growing, and there are just sitting around waiting for some signal.

{***Noah***}

That was our conversation with Eric Rubin about tuberculosis.

{***Amie***}

That’s all for this week’s episode, but as always you can listen to past episodes by subscribing on iTunes or Stitcher…or stream this podcast anytime at soundcloud.com/harvardpublichealth.