Tuberculosis and the Scientist
The third and final part of our trilogy on Tuberculosis – the scourge and solutions
“The name of my village is Nimdaha.”
“Sorry, dada, Nim-?”
“Nimdaha – falls in Bardhaman district of West Bengal. I am a farmer. Even now my eyes light up in the city. I look in wonderment at everything – suits a scientist, you can say. I remember as boys when we were working in the fields, to our mind the camera was a thing of high society. If anyone came with a camera or a tape recorder to our village we’d be summoned from the fields by the elders. One day, someone brought a tape recorder from Kolkata. God, there were at least 200 of us who rushed back to the village to see this kaller gaan. Abandoned the oxen, the plough, haal, everything – even the dabba and surahi. Kaller gaan means song of the machine”.
“What prompted you to return to India and start your research on tuberculosis?” I ask Gobardhan Das, 46, a tuberculosis researcher.
“I was in America for 12 years, first as a post-doc at Yale Medical School, and later as a senior scientist at Aventis. Even from there I tried to do whatever possible for my village. But the distance was too much. Sometimes you think you have everything – car, house, swimming pool – but you have nothing. I missed my country. I felt India needed me. What was I doing there? Yaa…came back.”
“And why tuberculosis?”
“No one dies of TB in America. But here – it’s scary, what is happening: MDR, XDR, and now TDR – where will it all end? There’s no vaccine, hardly any new drug – and that’s not good. On the other hand, not much is known about the immunology of TB infection. Once we understand how TB utilises the host machinery for its survival, we can design some cunning new stuff. Anyhow, that was the thinking.”
As with any disease, there are essentially three ways to combat it. One can discover or develop a drug against it; one can formulate a vaccine – live, heat-killed, or sub-unit; and finally, one can prime our immune system to fight it using immunotherapy.
Tuberculosis is no different. There are almost three-dozen drugs – developed over the past 50 years – that can kill tuberculosis. Without exception, the TB bug has found ways to dump each one of them by the wayside.
When would it dawn on us that we really are at the bottom of the pyramid?
An average human body contains 1 quadrillion squigglies. Yes, bugs complete us. That’s until they begin to turn dangerous. And resistant.
The first resistant strain of tuberculosis was detected as early as five years after the mass-scale administration of Streptomycin in the late 40s. There has been no new anti-TB drug for the past 50 odd years.
To get a better idea of where we stand, I ask Tanjore Balganesh, another tuberculosis researcher. He should know. A sharp, no-nonsense man, he headed the R&D unit of AstraZeneca for close to a decade. Now he runs the government’s anti-TB drug discovery platform.
“India harbours the largest number of MDR cases”, says Balganesh. “Our success rates are poor and our armament is abysmal. The Quinolones [a family of molecules that have long served as anti-TB drugs] are a losing proposition due to wide-spread resistance. In this scenario we are fighting a losing battle. The need cannot be overestimated.”
The problem is as much to do with luck as it is with science. As I write, millions of compounds and small molecules are being screened by hundreds of pharma companies around the world, in the hope that some among them will turn out to be anti-TB marketable drugs. This, so-called compound library panning has been going on for decades, and the results are pitiful.To check out details see this link – http://www.newtbdrugs.org/pipeline.php
Yup, that is it – that’s the current pipeline.
But lives are at stake and beggars can’t be choosers.
“There is a silver lining, though”, comforts Balganesh. “Two new drugs have completed Phase 2B studies, one of which, Bedaquiline, has received Schedule H clearance allowing it to be marketed for use on critical patients. There are desperate cries for the drug. A Phase 3 trial, however, has to be completed within a specified time.”
Bedaquiline offers great hope for patients suffering from drug-resistant tuberculosis. Like most other drugs, it was mined from a gigantic library of small molecules (see Bibliography). Johnson & Johnson, the company that unearthed this pink diamond, advocates careful use of this beauty or it warns that a similar fate – that of other first-line anti-TB drugs – awaits it: wide-spread resistance. In other words, we cannot afford to rejoice yet.
“The second drug, Delamanid”, adds Balganesh, “has also completed Phase 2b and will probably follow the same track. A couple of other compounds, PNU1000008 and PA824 [all referenced below] are approaching Phase 2b trials.”
Delamanid is yet another VVS1 diamond that was languishing in the small-molecule coalmine until the Japanese discovered it. The New England Journal of Medicine published recently a large-scale study based on Delamanid that should warm the cockles of diamond-merchants like Balganesh.
Not quite.
“The problem is of belling the cat”, he worries. “If any of these new drugs are used as an add-on to the existing regimen we can be sure of losing the drug within the next five years. What is the combination that we can employ to preserve these compounds, is the billion-dollar question. None of us have a clue. Are we going to allow the end-user to determine the same, or is this going to be approached in a systematic fashion? We have to find a new combination to save any new drug.”
On the vaccine front, things aren’t exactly rosy either.
The only approved vaccine against TB is almost 100 years old. BCG – short for Bacillus Calmette-Guérin – is a strain of Mycobacterium bovis that has lost its bite. Its efficacy is variable: non-protective in adults but protective against a deadly form of TB in children. There are multiple reasons for this variance, the principal being that no “true” single strain for BCG exists anymore. And yet, no one has bettered BCG in all the years that scientists have scoffed at it. Camlette rules ineffectively but he still rules.
That said, the TB Vaccine Initiative, which falls under the StopTB Partnership, has an ambitious goal: “…to reduce the global incidence of TB disease to less than one case per million population by 2050”. As of 2011, there are 15 vaccine candidates undergoing various stages of clinical trials, 5 under pre-clinical studies and 33 that are “candidate vaccines”, i.e. haven’t yet reached the earlier two stages (http://www.tbvi.eu/fileadmin/user_upload/Documenten/
News/TB_Vaccine_Pipeline_2011_FINAL03042012.pdf). Among these is a candidate from India, Mycobacterium Indicus Pranii.
Originally isolated from patient sputum by Pran Talwar, pranii, or M w as it was known earlier, is a poor harmless cousin of the dreaded Mycobacterium tuberculosis. Pran reported that mice inoculated with heat-killed pranii were protected against an infection of TB. Follow-up studies over decades have since shown that pranii protects mice and guinea pigs against TB a little better than BCG. Pranii has since been approved for human use in leprosy patients. However, it is against TB that it must prove its mettle. It may be that pranii gets qualified as a vaccine to treat rather than prevent TB, i.e. a therapeutic vaccine and not a preventative one.
In their desperation, scientists have also tried to redesign BCG – make it superior – but results have been mixed. The problem is partly because of the kind of immune response that BCG elicits. It is weak. A lot of proteins that are otherwise present in TB are absent from BCG, and so naturally, the immune system of a TB patient does not possess antibodies to these “missing” proteins. As many as 4 vaccines currently undergoing clinical trials are BCG vaccines with added bits and pieces. Of these, the recombinant BCG vaccine from Max Plank, Germany, called VPM1002, holds good promise.
The third route to combating TB is through immunotherapy. As the name suggests, the idea is to cure the patient by modulating his immune system, our first line of defence against any pathogen. Molecules that do this “tweaking” are called immunomodulators and have been given amusing, star-waresque names: interleukins, interferons, cytokines, etc. The whole vast subject of Immunology is the study of these molecules and how they modulate our body’s fight-back.
In December of 2010, our farmer-turned-scientist shook the world with his discovery. Gobardhan and his team had stumbled upon a long sought-after secret – how TB evades our immune system. It turns out TB recruits our own stem cells – called mesenchymal – to build a mote around its fortress. As a result, our immune system, even with its battery of mortar-spewing cannons and loyal star-war robots simply cannot get to that fortress. Worse, this recruitment results in an immune modulation that helps preserve a status-quo between the warring sides; eye-to-eye ceasefire, if you like. And the bug lives to die another day. Cunning little devil.
Gobardhan’s discovery is as big as they come in the field of TB Immunology. Understandably, it went viral (er, bacterial). The Telegraph: TB ‘recruit’ riddle unravelled; New Scientist: Stem cells in TB protection racket; ABC News: TB defence could be Achilles heel; Deccan Herald: Scientists find how TB bacteria evade drugs; Reuters: Some stem cells protect TB bacteria; The Hindu: How the TB bug hijacks our stem cells for its survival; USA today: A potential drug target for tuberculosis.
The American Museum of Natural history (with support from The Proceedings of the National Academy of Sciences USA) even made a short film on the discovery.
“Describe the eureka moment, dada. Were you in the lab when the student brought over the results?”
“It’s well known that the bug survives within susceptible hosts by inhibiting host immune responses, but it was not clear how. When we infected mice with TB, we found a dramatic inhibition of T cell [our immune system’s fighter cells] responses in infected organs. Surprisingly, we also found a massive cellular infiltration in spleen and lung. There was something about those infiltrated cells. What they were and how they thwarted our body’s immune attack, was a mystery though. We tried to stain them with all the damn markers we could lay our hands on, but nothing. Then one evening, I was reading a paper where they reported that mesenchymal stem cells can inhibit T cells. That was it! I rushed to the lab at 3 a.m. and designed the experiment. As soon as my student came in at 9, I asked her to stain the cells with a specific marker immediately. At 11:30 a.m. we were both sitting in front of FACS [a laser-assisted machine that can count and sort different type of cells]. That moment, when we saw huge numbers of cells being Sca-1 positive…I felt dizzy. The student was there so I couldn’t jump up and down. She was anyhow smiling ear-to-ear. No, no one said Eureka!”
Their discovery has since been confirmed by other research groups. In January of this year, a group at Stanford showed that the bug not only recruits the mesenchymal stem cells to form a barrier around itself, it actually hunts the cells down, all the way to the bone marrow, and once in clear sight slips among the crowd to evade detection by our immune police. The Hindu reported the Stanford finding – At last, hideout of dormant TB bacteria found – but failed to quote Gobardhan’s work.
“Our study clearly demonstrates how this stem-cell-TB reservoir is maintained in the body and how the latent infection arises”, says Gobardhan. “Today, one-third of the global population is infected with latent TB, which is simply a reservoir for an impending epidemic. I think to eliminate or to treat latent TB, one has to target the mesenchymal stem cells. There are many ways it can be done including altering their migration pattern, or changing their immunosuppressive activity. Many laboratories worldwide are now following our lead, and I know some pharma companies in the US that have already begun to investigate its money-spinning worthiness. It’s probably opened up a new field in infectious disease research, like how Kanury’s work did.”
Gobardhan is alluding to a recent landmark study by Kanury Rao and his colleagues that was published in the journal, Cell. They charted out a profile of all the host genes that were aiding TB, and found that as many as 250 were actively helping the bug survive inside our body. As a reciprocal gesture, the bug had promised the host that it will lie low for decades and not wreak havoc the minute it sneaked in. As bizarre as it gets – us helping out?! The evolutionary process and the principles of mutual benefit cost assessment are to blame, I suppose. All in the family, little man!
“Did you patent your discovery?” I ask Gobardhan.
“No. I do not believe in patenting. If what I do can in any way benefit humanity, I don’t see a business component.”
“Why do you think only 10% of Indians exposed to tuberculosis go on to get the disease? Is our immune system working differently from other people?”
“Hah, probably not – the 10% figure is true for all populations. But as far as we are concerned, there could be several reasons. First, we are always exposed to environmental Mycobacterium [harmless cousins of TB, third or fourth removed], which may actually provide us with a low level of natural protection. Second, we consume lots of turmeric which is a fantastic immunotherapeutic agent. In fact, this has been proved experimentally. Haldi is the best discovery an Indian has ever made.”
“Yes, and he or she never patented it.”
“Precisely my point.”
“Do you think we’d ever beat it, dada? Tuberculosis?
“Of course, we will. I wouldn’t be doing science if I thought it’s all hopeless.”
Dada is right. The situation is alarming. But that’s what alarms are for – to wake people up. Except that this time round, the alarm has sounded not just for the scientist but also for the doctor and the journalist. Together the war can be won. What is a wild and thrashing beast can be tamed, taught a few tricks. Sit! And now shoot!
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Bibliography:
On mesenchymal stem cell discovery:
On host genome profiling:
On general articles and TB pipeline:
On Bedaquiline:
On Delaminid:
On PA 824:
On TB immunotherapy:
On TB vaccine:
Disclosure: The author is a colleague of Dr. Gobardhan Das at ICGEB and is collaborating with his group on research projects related to tuberculosis.
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