On this edition of FOCUS In Sound, we’re going to learn about a devastating infectious pathogen – Mycobacterium tuberculosis, a bacterium with incredible staying power and, unfortunately, considerable killing power as well. Although we might think of it as a somewhat old-fashioned disease, tuberculosis is still an enormous global health problem, with 15 million new cases every year and as many as 3 million deaths worldwide. Also, up to one-third of the world’s population, that is, as many as 2 billion people may be latently infected with tuberculosis. Despite the many advances in biomedical research over the past several decades, it is still the case that very little is known about how the tuberculosis bacterium works. Joining us on FOCUS In Sound is a young investigator who is working to change that by conducting basic research on the tuberculosis bacterium. By characterizing the pathogenesis of the disease and enhancing the ability to diagnose it, the ultimate goal of her group’s work is nothing less than the ultimate eradication of this infectious scourge. Dr. Sarah Fortune is the Melvin J. and Geraldine L. Glimcher Associate Professor of Immunology and Infectious Diseases at the Harvard School of Public Health. In 2012, she was the recipient of a 5-year, $500,000 grant as one of the Burroughs Wellcome Fund’s Investigators in the Pathogenesis of Infectious Disease.
Transcription of “Interview with Sarah Fortune”
00;00;10;10 – 00;00;50;14
Ernie Hood
Welcome to Focus In Sound. The podcast series from the Focus newsletter published by the Burroughs Wellcome Fund. I’m your host, science writer Ernie Hood. On this edition of Focus In Sound, we’re going to learn about a devastating infectious pathogen Mycobacterium tuberculosis, a bacterium with incredible staying power and unfortunately, considerable killing power as well. Although we might think of it as a somewhat old fashioned disease, tuberculosis is still an enormous global health problem, with 15 million new cases every year and as many as 3 million deaths worldwide.
00;00;51;00 – 00;01;26;21
Ernie Hood
Also, up to one third of the world’s population that is as many as 2 billion people may be latently infected with tuberculosis. Despite the many advances in biomedical research over the past several decades, it is still the case that very little is known about how the tuberculosis bacterium works. Joining us on Focus In Sound is a young investigator who is working to change that by conducting basic research on the tuberculosis bacterium, by characterizing the pathogenesis of the disease and enhancing the ability to diagnose it.
00;01;27;04 – 00;01;53;21
Ernie Hood
The ultimate goal of her group’s work is nothing less than the ultimate eradication of this infectious scourge. Dr. Sarah Fortune is the Melvyn J and Geraldine L Glimcher, Associate Professor of Immunology and Infectious Diseases at the Harvard School of Public Health. She received a B.S. in Biology from Yale University and her M.D. from Columbia University’s College of Physicians and Surgeons.
00;01;54;06 – 00;02;30;04
Ernie Hood
She completed her residency in Internal Medicine and Fellowship in infectious diseases at the Brigham and Women’s Hospital and Massachusetts General Hospital. Dr. Fortune is supported by awards from Howard Hughes Medical Institute, the Doris Duke Charitable Foundation, the National Institute of Allergy and Infectious Diseases, and a New Innovator award from the National Institutes of Health. In 2012, she was the recipient of a five year, $500,000 grant as one of the Burroughs Wellcome Funds Investigators in the Pathogenesis of Infectious Disease.
00;02;31;00 – 00;02;33;19
Ernie Hood
Sarah Fortune, welcome to Focus In Sound.
00;02;33;29 – 00;02;35;21
Sarah Fortune
Thank you so much. It’s a pleasure to be here.
00;02;36;18 – 00;02;42;17
Ernie Hood
Why, Sarah, has there been so little progress at this point in combating tuberculosis?
00;02;42;25 – 00;03;07;27
Sarah Fortune
That is a good question and in some ways surprising. We have made enormous advances in many fields. Tuberculosis has been understudied in part because it affects the rest of the world, not so much the United States. In your introduction, you mentioned something like a third of the world is estimated to be latently infected with TB. Most of those people are in Africa, India and China.
00;03;08;02 – 00;03;36;13
Sarah Fortune
And so tuberculosis hasn’t been a funding priority until relatively recently in the United States. And then tuberculosis has been really hard to work with. When we work with tuberculosis, we work in what’s called a biosafety level three facility, which is not quite like the containment facilities in the movies outbreak or something, but is pretty close. So, you know, everybody’s wearing a spacesuit and works in very scripted, stereotyped fashion to be safe.
00;03;36;25 – 00;03;57;07
Sarah Fortune
And progress is slow. And so the combination of those, a lack of funding and the constraints of working in a biosafety level three facility have really made progress slow. Why do we not have a better handle on tuberculosis? We don’t have a better handle on tuberculosis because we lack all of the critical tools that we take for granted in other areas of medicine to control the disease.
00;03;57;17 – 00;04;16;02
Sarah Fortune
So we can’t diagnose people well. Once we can diagnose people, people have to take antibiotics for something like 6 to 12 months to be cured of their infection and there is no effective vaccine. And so the whole armaments area of tools that we would use to fight an infection we don’t have for choices.
00;04;16;27 – 00;04;32;11
Ernie Hood
So why does TB diagnosis remain poor? I understand that in many parts of the world it currently takes about six weeks to get an initial diagnosis and another six weeks or so to determine whether it’s a drug sensitive or drug resistant strain.
00;04;32;28 – 00;04;56;09
Sarah Fortune
You are absolutely right. And that’s many parts of the world, like Boston, Massachusetts, where I live, the tuberculosis bacterium grows very slowly. And traditionally in microbiology diagnostics, we diagnose an infection by throwing the bacterium up and then figuring out what it is. And then exposing it to the antibiotics that you would take and asking if that bacterium lives or dies.
00;04;56;21 – 00;05;28;25
Sarah Fortune
And because the tuberculosis bacterium grow so slowly, that whole process takes something like three months. And that’s not a resource allocation issue. That is literally how long that process takes. So it would take the same amount of time in Mass General Hospital as it would in Johannesburg and to solve that problem. Therefore, we need new tools. We need really completely revolutionary new ways of diagnosing the infection that don’t rely on standard culture based diagnostics.
00;05;29;12 – 00;05;38;03
Ernie Hood
I see. Well, where do we currently stand in our ability to treat tuberculosis? Have there been advances or is it still very challenging to treat?
00;05;38;16 – 00;06;06;10
Sarah Fortune
TB is still challenging to treat, although there has been investment over the last decade in new drug programs and that is beginning to show fruit. So for the first time in actually, I think almost three decades, there are new antibiotic compounds coming up and they are specifically for TB. So it’s possible we’re going to have new drugs as of two or three years from now, and that is great.
00;06;06;16 – 00;06;23;13
Sarah Fortune
However, all of the new drugs that are emerging are drugs that will still take six month or a nine month or a year long course to cure somebody. So what you’d really love is to treat TB the same way you treat something like you’re at your infection. You go, you get a seven day course of antibiotics and you’re done.
00;06;23;22 – 00;06;28;13
Sarah Fortune
And for that, we’re going to need really different kinds of drugs. And we’re not even close to that.
00;06;29;13 – 00;06;41;13
Ernie Hood
Well, I know that drug resistance is also very much of an issue. What is it about the tuberculosis bacterium that makes it so incredibly resilient and so often resistant to drug therapies?
00;06;42;00 – 00;07;05;18
Sarah Fortune
Okay, that’s a great question. And the short answer is we don’t have any idea. And just to kind of give you a sense of how incredibly hardy this bacterium is, we can expose the bacterium to antibiotics that you would take to which the organism should be sensitive and you will only kill a portion of the population all of the time, even in a culture dish where everything is perfect.
00;07;05;29 – 00;07;31;10
Sarah Fortune
And we really don’t understand in that population of bacteria, what makes one bacterium susceptible to antibiotics and one bacterium tolerant of those antibiotics. And really that’s one of the major focus of our research, is to try to understand essentially bacterial individuality, what makes one bacterial cell different from another and why you can kill off them easily. And what makes those kind of long lived cells special.
00;07;31;29 – 00;07;38;19
Sarah Fortune
We hope by doing that we’d be able to develop better interventions to really get rid of those long live cells quickly.
00;07;39;20 – 00;07;59;14
Ernie Hood
With that in mind, let’s move on to your laboratories. Microbiological research on tuberculosis. I understand that your efforts are actually concentrated in three specific areas. So I’d like you to give us a brief overview of each one, starting with the genetic and epigenetic variation.
00;07;59;23 – 00;08;21;00
Sarah Fortune
I kind of introduce the idea that we think individual bacterial cells are special and distinct from one another, and just like you and I are distinct from one another, or really the cells in our body, our hair cells are different than our skin cells, and we kind of take that for granted. But I think when you look at a population of bacterial cells, it’s easy to imagine they are all the same essentially.
00;08;21;11 – 00;08;41;13
Sarah Fortune
So we’ve been trying to understand the mechanisms by which bacterial cells differentiate. And a lot of what we have done is build on paradigms that have been developed in people studying, often eukaryotic cells like the cells in our body and trying to understand why our hair cells are different than our skin cells. And that might be at a genetic level.
00;08;41;13 – 00;09;15;24
Sarah Fortune
Their DNA is different. That might be at an epigenetic level. So there is something that generates long lived differences between cells such as histone changes and the proteins that bind the DNA. Or there can be higher frequency mechanisms. And we have broadly looked at all of those. So we’ve started kind of with the foundation by looking at genetic diversification and used a whole range of approaches, a lot of whole genome sequencing of of isolates from different conditions to try to comprehensively map the rates and locations of genetic diversification.
00;09;16;08 – 00;09;45;16
Sarah Fortune
The upshot of that is the rates are higher than we’d expect. They kind of occur in different stages of disease than we might have expected, but they’re not sufficient to explain the diversity of cells that we see. If we just look at cells under a microscope where they’re we see really they’re very phenotypic different. And so we’ve been looking at other mechanisms by which those cells might differentiate, and that has brought us to epigenetic diversification and high frequency diversification.
00;09;45;22 – 00;09;56;23
Ernie Hood
In the course of that line of research. What have you been able to find out about the diversification that affects drug resistance? For example.
00;09;57;01 – 00;10;21;08
Sarah Fortune
The cells differentiate at many different rates using many different mechanisms. And so what’s been totally startling is that when we started, the presumption I think in the field was that a population of mycobacteria were very homogeneous and really not very plastic. So they didn’t really actually have a lot of capacity for diversification. And we have uncovered multiple mechanisms by which that diversity arises.
00;10;21;12 – 00;10;35;29
Sarah Fortune
One of the simplest is that it turns out that like a bacterial cell, which kind of you can think of as like a cucumber is not symmetric. So one end of the cell and the other end of the cell are not the same. So the stem into the cucumber in the bud end of the cucumber are not the same.
00;10;36;09 – 00;10;57;23
Sarah Fortune
And so when that cell divides and it would kind of break in the middle, it creates daughter cells that are different. They inherit different cellular contents and they function in different ways. And we’ve been talking about antibiotic susceptibility. And one of the very simple ways in which they’re different is they’re differentially susceptible to different antibiotics that kind of diversity arises incredibly quickly.
00;10;57;29 – 00;11;21;12
Sarah Fortune
And so if you start with one cell, by the time you have a little flask of cells, you have daughter cells that are really, really different from one another in terms of their susceptibility to drug. Just from this very simple mechanism. And then there are layered on top of that, slower mechanisms of diversification that are a little bit more stable, that allow the cell to have a longer lived identity.
00;11;21;14 – 00;11;32;17
Sarah Fortune
But that’s still not changing its DNA. And then at the kind of slowest level, the cell is still mutating and mutating in ways and at rates that we wouldn’t have expected.
00;11;33;07 – 00;11;39;28
Ernie Hood
So this is actually kind of a unique challenge for this type of research. I take it it’s a very tricky bacterium.
00;11;40;12 – 00;12;12;29
Sarah Fortune
I suspect every bacterium is tricky in its own ways. But because TB has established such a successful relationship with us, its human host TB, it only lives in people. It is exquisitely adapted to survive in people. And all of those mechanisms of diversification really play into that relationship. And so its uniqueness is that all of that diversity really is part of its ability to cause prolonged infection.
00;12;13;19 – 00;12;52;12
Sarah Fortune
I think that for many people in the United States especially, it may not be clear what a problem drug resistance is. It’s just important to recognize that in Mumbai over the past year, strains of tuberculosis have emerged that are resistant to every antibiotic we have. It’s a real and immediate threat in parts of the world and something that we have to as new drugs come online, as these new compounds are really coming to the market, we have to understand and in parallel, the process of drug resistance such that we can protect the few drugs that we have otherwise were going to have an untreatable infection spread from person to person, just kind of willy nilly.
00;12;52;20 – 00;13;03;22
Ernie Hood
So, Sara, what types of methodologies do you and your colleagues employ in working to define these bacterial determinants of variability that you’ve been discussing?
00;13;04;07 – 00;13;36;08
Sarah Fortune
My lab has used a whole range of technologies ranging from microscopy to whole genome sequencing. We’re really enchanted, honestly, with kind of the new high throughput technologies, because one of the funny things about tuberculosis is that it’s not really closely related to a lot of bacteria that have been well-studied. So you may have heard of E coli or bacillus subtilis and those are what we call model bacteria and they are super well-studied and we know a lot about them.
00;13;36;18 – 00;14;13;27
Sarah Fortune
And mycobacteria are as closely related to coli as we are to plants. And a lot of the paradigms about how a cell works in E coli, it’s really just on hold in mycobacteria. And so we have a huge, huge, huge knowledge gap that we have to infill quickly and honestly, we just can’t be sitting around for the next 20 years figuring out how that that cell works and what these new technologies and new high throughput technologies, at least hold the promise of is really rapidly filling in the knowledge gap in a kind of comprehensive fashion without doing the one by one by one experiments that have built this beautiful picture of the workings of a
00;14;13;27 – 00;14;28;07
Sarah Fortune
model organism. So we’ve really been trying to make use of them and figure out how to put together all of that complex data in a way that makes sense to us and that allows us to ask questions about how the cell works.
00;14;28;25 – 00;14;35;09
Ernie Hood
Well, Sara, one thing that’s coming through loud and clear in what you’re telling us is a real sense of urgency with this disease.
00;14;35;25 – 00;15;07;12
Sarah Fortune
Yes. TB is a really an epidemic in some parts of the world. If you go to Durban, South Africa, at any given point in time, one in 100 people has has TB active tuberculosis. Here in Boston, Massachusetts, it’s about one in 100,000 people. So the rates in some parts of the world are extraordinary, and that’s active disease. If you go to Durban, South Africa, I think you could assume that almost everybody, a huge portion of the population is latently infected and there’s just this epidemic of active disease.
00;15;07;12 – 00;15;28;07
Sarah Fortune
And this is a region of the world where highly drug resistant strains are emerging. And so it is an enormous and immediate problem for people who don’t remember this. TB is is an aerosol infection. That means I cough the bacteria, hang out in the air and somebody else breathes them in. And that’s how it’s transmitted. It’s transmitted from person to person in a very promiscuous way.
00;15;28;07 – 00;15;32;09
Sarah Fortune
And that gives really the capacity for very large scale infection.
00;15;32;29 – 00;15;43;20
Ernie Hood
Well, I understand that one result of the new technologies you’ve been able to deploy, as you described as in so many other fields, is a mountain of data to sift through.
00;15;44;08 – 00;15;44;19
Sarah Fortune
Yeah.
00;15;45;09 – 00;15;50;04
Ernie Hood
Tell us about that problem and the unique approach you’ve undertaken to help solve it.
00;15;50;24 – 00;16;22;00
Sarah Fortune
Any of these new technologies, be they the whole genome sequencing technologies or the live cell imaging technologies, generate huge amounts of data, and we have to be able to resolve that into some sort of biologic picture that makes sense. And so it poses all sorts of challenges for us, computational challenges, and then very simple challenges, like we take movies of bacteria and we try to understand why one bacterial cell is different from another by watching them in movies.
00;16;22;13 – 00;16;38;01
Sarah Fortune
If you think about how you would do that in a normal movie, you would just kind of with your eye track those and say, okay, I can see this one has turned green and this one has turned red. You know, something simple like that. But if you’re going to do that for hundreds of thousands of images, you need an automated way to do that.
00;16;38;10 – 00;17;04;07
Sarah Fortune
And it’s really hard, really hard to develop an automated way that you can customize for your next question. And so one of the ways that we’ve been exploring, it’s crowdsourcing that image ID in order to enable people’s eyes to do what your eyes do well, which is track things and find differences and which is really hard to teach a computer how to do even in this day and age.
00;17;05;06 – 00;17;10;05
Ernie Hood
So, sir, is the crowdsourcing beginning to bear fruit and actually give you the information you need?
00;17;11;00 – 00;17;38;05
Sarah Fortune
It has been very exciting. And for those people who’ve been thinking about crowdsourcing, actually crowdsourcing has been is being used a lot in commercial image analysis. So, for example, companies will have stacks of text that the scanner can’t quite read. And so people will go in and say, is this a W or an N or something? Or they’ll have faces and they’ll want to know, are these people happy or sad?
00;17;38;05 – 00;18;07;15
Sarah Fortune
And they’ll have crowdsourcing teams that will do that. Those are big commercial companies, Fortune 500 level companies that have a lot of image processing needs that are interfacing with the crowdsourcing world. And what we’re trying to figure out now is how the average academic’s lab, which is working at a much smaller scale, quite frankly, with much more beautiful and interesting images, how we can interface in an effective manner with what is essentially a commercial crowdsourcing world.
00;18;08;16 – 00;18;31;27
Sarah Fortune
It’s been a little bit of a challenge, but it’s exciting. The initial efforts have totally borne fruit and given us a first level of analysis in. We have then essentially wanted to push that to the next level to be able to develop a kind of suite of customizable tools that we could ask the crowdsourcing worker at home just to do customizable tasks.
00;18;32;05 – 00;18;33;21
Sarah Fortune
And that’s what we’re trying to do now.
00;18;34;18 – 00;18;47;07
Ernie Hood
Sarah How might your research efforts, not only the crowdsourcing but everything you’re up to in your lab lead to new diagnostic capabilities or even improvements in treatment?
00;18;48;06 – 00;19;19;04
Sarah Fortune
We care a lot about new diagnostics, and actually, if I had a goal for the lab, it would be that we would really, at least as part of a collaborative effort, change the face of TB Diagnostics. And TB Diagnostics sound not so glamorous, but as I alluded to earlier, it’s critically important that people are diagnosed early before they have a chance to spread this infection to lots of people that the diagnostic be easy and cheap and fast and essentially that just doesn’t exist now.
00;19;19;13 – 00;19;44;22
Sarah Fortune
And so what we’re trying to leverage is in our ability to work with individual bacteria and handle them and track them easily. And and use that technical capacity in collaboration with engineers to track and sort of translate that technical capacity into a simple diagnostics that would essentially be able to see small numbers of bacteria and recognize them as tuberculosis quickly.
00;19;45;08 – 00;19;51;01
Ernie Hood
And when would you expect, uh, that line of research to do better translation or for.
00;19;51;18 – 00;20;12;04
Sarah Fortune
The process of deciding when you’re ready to say to do something like start a company is not entirely clear to me. So we’re kind of at that point, are we ready or deciding whether we’re ready or not? And I think we’re not quite sure if we’re ready or not. We’ve made a lot of progress to the point where we can ask the question, are we ready to go?
00;20;12;04 – 00;20;21;05
Sarah Fortune
Are we ready to form a company and, you know, build a device? And I don’t have an answer for it yet. I would love to say yes, but maybe we have a little bit more work to do.
00;20;22;01 – 00;20;27;12
Ernie Hood
I’m sure that’s going to keep you busy in the laboratory and, uh, keeping keep you coming to work every day.
00;20;27;13 – 00;20;39;17
Sarah Fortune
Yeah, well, actually, science is wonderful in terms of keeping you coming to work every day, because every day is new. And every day you get to decide what you’re going to do and try something new. And it’s really it’s fantastic.
00;20;40;01 – 00;20;44;13
Ernie Hood
Well, sir, how did you happen to find yourself in this particular line of research?
00;20;44;24 – 00;21;05;24
Sarah Fortune
I am a doctor by training, and I went to medical school at Columbia, which is in New York City in the early 1990s. Seems a whole long time ago. But in the early 1990s, that was when, you know, HIV was epidemic in New York and we didn’t have antiretroviral drugs. We had lots and lots of new HIV infections.
00;21;06;04 – 00;21;30;20
Sarah Fortune
And exactly at that time we had outbreaks of multi-drug resistant tuberculosis where the United States had thought that we had really solved the problem. And so in our hospitals, in the armory, across the street, in the prisons in New York, HIV infected people, and then doctors and nurses and staff were getting drug resistant tuberculosis and dying. It was incredibly formative for me.
00;21;30;20 – 00;21;52;03
Sarah Fortune
And at the time, from sort of a naive perspective, I saw a lot of attention being paid to HIV. And I kind of thought, Oh, we’ll have that problem well under control by the time I finish all of my medical school and clinical training and postdoctoral fellow training. And what is not clear to me is whether we’re going to have the tuberculosis problem solved.
00;21;52;11 – 00;21;55;20
Sarah Fortune
And so that’s what I’m going to work on. And that’s where I am.
00;21;56;18 – 00;22;02;13
Ernie Hood
Well, last but not least, Sara, where is your research headed from here? What are what are your next steps?
00;22;02;19 – 00;22;25;23
Sarah Fortune
I’ve talked a lot about bacterial individuality and how that may determine whether one bacterium dies in the face of drugs or survives in the face of drugs. The other big question in terms of bacterial individuality is how that changes the course of disease. And one of the really interesting things about TB is how variable the clinical course of disease is.
00;22;26;06 – 00;22;47;10
Sarah Fortune
If you have 100 infected people, about ten of those people will get active disease immediately and the rest will be what we call latently infected. So when we say a third of the world is legally infected, we mean they’re infected, but they’re not sick. Of those 90 people who are lightly infected, only another ten, let’s say, will get active disease during the course of their lifetime.
00;22;48;11 – 00;23;06;05
Sarah Fortune
That begs the question of what distinguishes the people who get sick from the people who don’t? And how could we make those people who get sick more like the people who don’t in the field have really thought of that question in terms of human differences. So I’m different than you, and that might make me susceptible or you susceptible.
00;23;06;18 – 00;23;29;05
Sarah Fortune
But we have been wondering whether or not it’s actually in part determined at the level of the bacterium. When people get infected, they’re getting infected by one or two bacteria. And so whether the one bacterium that I get is different than the one bacterium you get sets up a fundamentally different course of disease that plays out in these very different ways at a clinical level.
00;23;29;12 – 00;23;36;18
Sarah Fortune
If I had to articulate the next big goal, it would be to understand how bacterial individuality shapes disease course.
00;23;37;04 – 00;23;47;13
Ernie Hood
Sara you and your group are doing some fascinating and important work and we wish you the best of luck for continued success. Thanks so much for joining us today on Focus In Sound.
00;23;47;17 – 00;23;49;08
Sarah Fortune
Thank you so much. It’s been a pleasure.
00;23;49;21 – 00;23;59;06
Ernie Hood
We hope you’ve enjoyed this edition of the Focus In Sound podcast. Until next time. This is Ernie Hood. Thanks for listening.
