Why is TB still killing people?

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1:09This is CrowdScience from the BBC World Service. I'm Marnie Chesterton. This is the map that I've got. This is from the 1930s. I'm on an odd sort of treasure hunt through the corridors of University College London, blueprint in hand. Does that bear any resemblance to where we are now? Yes, this is like this. OK, it's that way round. So I think this is the entrance, where we came in, and then these rooms would be at the far end. This place used to be a hospital, it's now a lab, and lab manager Georgia is kindly helping me pinpoint the spot where a very famous writer died. So we know that we're roughly in the right zone.

1:58Yes, yes, unfortunately we don't know where the room is. It is the closest we can get. OK, I'm calling it. This is the building, this is the wing, if not the room where George Orwell died. Orwell, famous for his dystopian novels Animal Farmer 1984, 1984, died not in room 101, but room 65, here in London, in 1951, of tuberculosis. It's weird being this close to where he died, and he was only 46, which is depressingly no age at all. And he wasn't unusual. Tuberculosis, or TB, has killed many millions. Russian playwright Anton Chekhov, former American presidential first lady Eleanor Roosevelt, Polish composer Chopin, Nelson Mandela caught it whilst imprisoned in South Africa but thankfully recovered.

2:54Countless poets and presidents from every continent have not been so lucky. But now, in some parts of the world, like here in the UK, it's a disease of the past. Globally, it's quite a different story, which is why crowd science listener John in Tanzania has a question. Hi, CrowdScience. My question to the team is, why haven't we been able to cure TB? It's been there with us for a really, really long time, and we still haven't figured a way out of it. And John, you're a doctor, right? Yes, I'm a doctor. Very early in my career, but yes, I'm a doctor. So you see TB? I see TB. Almost every day I see patients with TB.

3:42And yet, this is a treatable illness. There's also a vaccine called the BCG. So why is John still seeing so many patients sick with it? That's what he wants our help with finding out. It's very, very common in our setting. I don't know if my stats are up to date, but this is something we learned in med school, is that among three people, at least one of us has the latent TB, the inactive form of TB. I've heard the stat of one in four around the world, but even one in four is just absolutely shocking. Yeah, one in four is still... Where's my BCG scar? It's somewhere on this arm. I was also checking, I don't have mine.

4:26I also have mine. I know this is audio, so let me say, at this point, John and I are trying to roll up sleeves to compare vaccination scars. But then he brings the sobering facts. In my practice, I have seen people as young as 17 dying of TB complications. And how catastrophic is it in your country? In the past one year, I worked in a government hospital. And that's where, in my world, for example, working in an infectious unit, at most we are 20 patients. You could be attending 12 or 10 half of the patients having TB. Are people scared of getting it or is it just part of life and, oh, I got TB?

5:08Actually, it's a very scary disease because when someone suffers from TB, you cough up blood and, you know, you get wasted. So when a person has TB, it's really something that people really are scared of. So Dr John sees TB cases all the time. It kills over a million people a year and a quarter of us has latent TB, the bug, but not the disease symptoms. And John's question is why? When we've had antibiotics to fight it since the 1940s, plus, as we discussed, we've both got our scars from the TB vaccine, the BCG, what's going wrong? To try and answer his question, I think we need to start with that vaccine, which takes me to an interesting plaque in the cathedral-like entrance to Paris's main medical teaching hospital.

6:04With me, a historian of bugs and drugs. So my name is Claes Gichelle. I'm a historian and associate professor working for the French National Institute of Health and Medical Research INSEAM in Paris. We're standing by a plaque. What is it for? So we're standing in front of a plaque commemorating the first vaccination in a human against tuberculosis, which was administered by Calmet in 1921. So BCG and it's the real milestone in the history of tuberculosis. The vaccine is called the BCG, B for bacillus and C and G for Calmet and Guerin, the French scientists who made it. The method behind this is a traditional French way of producing a vaccine, which means that you reculture the strain hundreds if not thousands of times in order to weaken it and to attenuate it.

6:55So your body no longer sickens from exposure to the pathogen. It could be a virus, it could be a bacterium, and still has the capacity to learn from exposure to it to produce an immune response. And BCG was manufactured on this premise. Calmet and his team, they transfer over to Arnst du Pasteur following the end of the First World War. And here they move into human trials. And this is exactly where this starts in 1921 here on the site. And how successful was the BCG? That is one of the big, I think, historical research questions of the 20th and 21st century. BCG as such is a revolution in the sense that there is now a vaccine against tuberculosis, but it's not entirely clear from the get-go how protective its effects are.

7:42Very soon also doubts get raised about efficacy, for example, in different age groups and at different stages of the disease. Nonetheless, BCG, I think to this day, remains the vaccine of choice when it comes to tuberculosis vaccination and it's rolled out alongside other interventions which usually center on antibiotic therapy for people who are suffering from tuberculosis and also people exposed to them and most importantly in areas where tuberculosis is really controlled in the long term, focusing on improving sanitation and nutrition of populations, improving overall health. So the vaccine did make a difference, but what I'm hearing is that there's a lot of room for improvement.

8:22Or, to put it in starker terms... The number of cases that you get of TB per year clearly shows that the vaccine doesn't really work. I'm sorry, what? Time to introduce our next expert. Hello, I am Max Gutierrez. I'm a group leader here at the Francis Crick Institute in London, United Kingdom. The Crick is one of the biggest biomedical labs in Europe. Here, Max studies what the TB bacterium does inside our bodies and how our immune systems attempt to fight back. TB is one of probably the oldest diseases. If you think about Egypt and the mummies, you know, people have recovered bacteria from the mummies.

9:05So this is really like an old disease. TB is a lung disease. So bacteria will go through your airways, you know, into the lungs. And then in the lungs will interact with your immune cells. And those interactions will define if your cells will kill the bacteria, or if the bacteria is able to, you know, replicate, divide and growth, and then, you know, trigger active TB. Ideally, the vaccine would steer the body towards the former approach, killing the bacteria rather than letting them develop into the disease. Max says the reality of the BCG vaccine is a lot more disappointing. It had some protection, but then clearly it doesn't work in adults.

9:48So the vaccine is still being used. And the reason why it's being used is because it protects children against something that is lethal, which is TB meningitis. So basically, it's tuberculosis going into your brain, which in newborns, you know, the mortality rates are very high. So people vaccinated at very early stages of life will be protected. But that protection will wane with time. And, you know, the number of cases that you get of TB per year clearly shows that the vaccine, you know, doesn't really work. And there are many, many, you know, groups around the world that are trying to improve the vaccine that we have or generating or developing a new vaccine.

10:30So because that's probably the only way we have to eradicate the disease. OK, so the vaccine doesn't work very well or it doesn't work in adults. Exactly. That's right. But that's not all we've got. We've got antibiotics. We've got antibiotics as well. Yeah. We've got a treatment. It doesn't matter if the vaccine doesn't work. We've got a treatment. That's right. What's wrong with that? So TB is if you get infected with what is called a strain that is sensitive, it's a curable disease. The problem is very complex because for that treatment, you need to use many antibiotics, at least three or sometimes four or even more.

11:14and then the treatment will last for up to six months and sometimes longer depending on the strain that you have. A minimum of six months of treatment with multiple antibiotics sounds gruelling to me. So what's it like to go through that? In Kenya's capital, Nairobi, in the Kibera district, TB is rife. In the local community clinic, CrowdScience found 42-year-old Janet.

11:47I began to fall ill last year in November. I started to cough, a cough that persisted for one month. I was coughing and feeling intense cold during the day. At night, I was coughing and sweating, and my body kept wasting away. I lost a lot of weight. From 80 kilograms, I weighed 64 kilograms. That's when I went to the hospital. I was tested and told that I had TB. For the treatment, I kept time when I was taking pills. I was advised to eat well and avoid stress. So I kept coming to the clinic for every appointment. I didn't miss even one. At the beginning, we were given the four-pill-a-day medication, then a smaller pill for each day, pyrodotin.

12:35But after a while, pyrodotin was out of stock, so it meant that a person had to buy it for themselves. but this other one was being given for free. I used to set an alarm so that I would take the medicine every night after my meals. I took the medicine every night until I finished my treatment. Sometimes it was very hard. Janet has now recovered but is reluctant to share her diagnosis with her friends. Now I am okay. I have no fever. I have a healthy appetite. I can smell properly. I am okay. People run away from you. They stay away. They fear that you can infect them. I didn't tell anyone that I had TB.

13:18So we have a vaccine, but it only really works on kids. We have a series of drugs to treat TB, but it's a long and arduous process. And the disease comes with social stigma. Plus, you may have heard of the growing resistance to antibiotics. Well, because tuberculosis has such a long treatment, there's plenty of time for bacteria to evolve resistant to the drugs. Which all adds up to the deadliest infectious disease we have in the world today. Coming up next, I'll be finding out how science is fighting back. Pop quiz! What's in your kids' lunchbox? At Whole Foods Market, they've already done the studying.

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14:59You're listening to CrowdScience from the BBC World Service, the show that answers your science questions. I'm Marnie Chesterton, and this week, listener John, a doctor from Tanzania, wants to know why we haven't cured TB yet. I've mentioned the problems with the treatment and the vaccine, and now we're going to turn to the bacterium that causes it, mycobacterium tuberculosis. I think we need to hear how it seems to hide out in a quarter of the world's population, while only causing disease in some people. Hi, I'm Dr. Dani Best. I'm a senior lecturer at the University of Surrey. My primary area of research is tuberculosis and mycobacterium tuberculosis.

15:45And I've been called by others in the field a bacterial dietician because I'm very interested in what TB eats and how it eats it, particularly with regard to surviving in the human host. A tiny bacterium is a living organism, and Mycobacterium tuberculosis needs feeding the same as the rest of us. And working out what it eats to make it a happy and virulent pathogen is Danny's speciality. Yes, I mean, it's a very challenging organism to work with because it grows very, very slowly, and so research in this area is very slow. but in in addition to that it's a real beast of an organism many pathogens produce very defined factors which help them produce disease but TB as it's evolved over many many many years with its human host really uses its whole genome to manipulate this host and cause disease so it's a very complicated organism and disease process.

16:58What Danny means is that every bit of the TB bacterium's genetic information seems to help it get into your body and hide there. We've mentioned that TB is a lung disease but in a cruel irony the bacteria choose to make their home in precisely the cells that are supposed to hunt out and kill foreign invaders. So the primary human host cell is the macrophage. So macrophages are derived from white blood cells and TB is able to survive within these cells and these are the cells that are really designed to kill invading bacteria and viruses. So TB has the audacity to survive within these cells and also grow within them.

17:44But it also can survive in other cell types. It can also survive extracellularly. What's mycobacterium tuberculosis doing whilst it's waiting for your immune system to be compromised so it can attack you? Well, I think the honest answer to that is we don't really know. Mycobacterium tuberculosis is very, very good at growing very, very slowly or not really seeming to grow at all. So we have this idea that's in this sort of quiescent state. However, the emerging evidence is that this may be a much more dynamic state than we realise. It's quite complicated. So, as you can hear, this is all quite difficult to explain.

18:31Danny is part of an international team looking at that mysterious quiescent, or sleeping, stage. What turns sleeping bacteria into disease-causing bacteria? In very new research, the team have discovered one particular gene, very common across many species, that's been weaponised by the bacterium. And they found that getting rid of this gene stops Mycobacterium from developing tuberculosis in the body. It's a small part of a very large and largely missing jigsaw puzzle on how Mycobacterium bacillus operates. And for me, I think understanding that basic biology is really important for the process of developing better therapeutics.

19:23Back at the Crick Institute, cell biologist Max Gutierrez shows me firsthand why TB research is hard going. So we're over at a different part of the creek now and it's quite a quiet corridor and we're stopped outside an impressively intimidating looking lab. I mean one of the windows and it's got sort of several layers of glass. I think that's quadruple glazing. No look it's got one TV but I can see the gaps. And the kind of outside window is bolted on. That's because the TB's in there. That's right. We work with a human pathogen and obviously you don't want that to go anywhere else and you want to contain it.

20:10What are the big questions that you're answering behind this glass? The main one is trying to understand how the treatment for TB takes six months at least. And we really want to understand why it takes so long and if we can reduce that time and if we can find antibiotics that works better. So, in fact, we don't know very well how the antibiotics we are currently using in the clinic work. You know, why, for example, it takes at least three different antibiotics in six months to cure a person. That's one of the areas that we work. But the other one that we are very interested is in those very early events that decide that a person develop a disease or actually phase that back and then clear the infection.

20:56This is one of the main areas we work here. That's called part of the innate immune response. Okay, so some people get the bacteria and they clear it out of their body. That's right. Yeah. Some people get the bacterium and it hides away in their body. Exactly. And then other people just get sick. Exactly. And we really don't understand why some of them are able to clear the infection, which is one of the main questions in the disease. That's a lot of quite basic questions. Yeah. Do we know much about the biology of this? Well, the biology of TB is very complex. It's a combination of a very complex biology with maybe not much support for research, but also very difficult to work with.

21:42And all of that leads to the fact that there are many fundamental questions, as you said, that we still don't understand. Fundamental science aside, what listener John wants to know is, what's the best way to fight this bacteria? Ideally, in the ideal situation, the way to eradicate TB will be to have a vaccine that works. So if we need a better vaccine, is anyone around the world actually working on one? My name is Angelique Luabea-Kanikani. I'm a research physician at the University of Cape Town. I'm working on a TB vaccine and I've been working at the University of Cape Town for 15 years now, doing TB research, running clinical trials, been working on many, many candidates of novel TB vaccine in the last 25 years at Satvi.

22:33But Satvi is South Africa Tuberculose Vaccine Initiative. I'm wondering what makes South Africa a good place to study TB and possible new vaccines? South Africa is one of the countries with the highest TB incidence in the world. If you look at, for example, 20 years ago, we were recording more than 600 ,000 TB cases per year. When you do a TB vaccine research, you need to do TB vaccine research when you have a huge problem. Because of the number of cases that we were having every year, it gave the possibility to evaluate in clinical trials novel TB vaccine because you can see the impact. What Angelique is saying is that in South Africa, because disease rates are so high, you really notice if a new vaccine in clinical trials is making a difference.

23:27You have to wait to see how many TB cases have been averted by the vaccine. Right. And we've established so far that the BCG doesn't really work. What are the alternatives in the pipeline? The front runner that we have now is the M72 vaccine. And that is a very exciting vaccine. Why? because it's the first vaccine that has shown efficacy signal of preventing disease in those who are infected. That vaccine was evaluated in clinical trials phase two eight years ago. We haven't seen a vaccine like that showing that level of efficacy. 50%, more than 50 % of people, It prevents disease. This vaccine, this M72 vaccine, is going to phase three.

24:16And we have recruited 20 ,000 people where we received this vaccine. And we are doing this phase three to confirm the signal that was seen in phase two. We don't know. It was seen in a small sample of people, 3 ,500, almost that number. We've seen that 50 % protection. For my ears, 50 % efficacy doesn't sound like it's very good. I want 100 % efficacy. Of course, we all wanted a higher. What we are expecting is the minimum that we are expecting for is 50%. It can be higher, right? It can be 60 % or more. We don't know if we're going to see the same signal in 20 ,000 people. But if the vaccine is successful, it's a game changer because if we have a vaccine with 50 % vaccine efficacy, this vaccine can prevent 75 million of TB cases over 25 years.

25:2075 million TB cases can be averted. 8.5 million of deaths can be prevented. Can I ask you a personal question? I know that your uncle died of TB this year. Does it make you angry that we haven't found something to cure TB sooner than we have? It made me sad. It made me sad. It made me angry. This is my uncle, but how many more were like my uncle? It took long. It took, in my opinion, it took too much time to diagnose the TB he had. It took much time to give the correct treatment. And for me, it's unnecessary death. and it's just a statistic. What makes me angry and sad is why is he a statistic?

26:12It shouldn't be. Can I make him more than a statistic? Can we name him? His name was Filemon and he was a teacher, a headmaster. Professor Angelique Lourab-Yakene-Kene bringing home that each TB death is a family tragedy, which feels avoidable when in theory we have a vaccine and treatment for this disease. What we've learnt is that in practice neither is up to scratch and in addition the uncomfortable answer to why we haven't cured TB lies outside the science. I asked every one of my experts why they think we haven't cured TB yet. TB is a disease of poverty, socioeconomic condition. We don't have a vaccine that works.

27:01Access to antibiotics and healthcare linked to poverty is one of the main obstacles that we have. And then the lack of funding for research and developing new drugs and new treatments is also going down. Many of the solutions aren't biomedical. They're to do with improving people's nutrition and housing conditions. Getting rid of TB entails very simply actually improving people's living conditions, nutritional status, access to clean water, access to good housing. It's very simple, but obviously one of the most complicated challenges when it comes to global health. And I think that is an entire separate episode of CrowdScience.

27:45John, thank you so much for asking this question. And over to you for the credits. That's it for this edition of CrowdScience from the BBC World Service. The question came from me, John, in Tanzania, and the programme was presented by Manny Chesterton and edited by Ben Motti. If you have a question for the show, please email it to crowdscience at bbc.co.uk. Thanks for listening. Bye. Thank you, John. And I should remind you that you can also send us a message or voice note on WhatsApp. app the number is plus four four eight thousand three one four seven seven three that's plus four four eight triple zero three one four seven seven three thanks for listening