Professor of Immunology and Infectious Diseases, University of Cambridge, UK
Almost one in four of the world’s cases of TB is in India and the disease is constantly adapting itself to outwit our medicines. Could the answer lie in targeting not the bacteria but its host, the patient?
Professor Lalita Ramakrishnan is a leading authority on the biology of tuberculosis (TB). She studies the disease – one which most people will know of as a disease of the lungs – using what at first sight seems an unusual model: the zebrafish.
“What most people don’t realise is that about 40% of human TB occurs outside the lungs,” explains Ramakrishnan. “It can infect the brain, bone, heart, reproductive organs, skin, even the ear. In fact, TB infection is a basic biology question, and this is the same in zebrafish as it is in humans.”
TB is caused by Mycobacterium tuberculosis, which is generally transmitted from person to person through the air. It has been around since at least the Neolithic period, but its prevalence in nineteenth century literature led it to be considered something of a ‘romantic’ disease. The truth is a long way from this portrayal. The disease can cause breathlessness, wasting, and eventual death. And while treatments do exist, the drug regimen is one of the longest for any curable disease: a patient will typically need to take medication for six months.
Professor Ramakrishnan is involved in a new trial, due to start soon that might allow doctors to reduce the length of this treatment. She is cautiously optimistic that it can be reduced to four months; if successful, however, it may eventually lead to treatments more on a par with standard antibiotic treatments of a couple of weeks.
The trial builds on work carried out by Prof Ramakrishnan and colleagues at the University of Washington, Seattle, before she moved to the Department of Medicine in Cambridge in September 2014, using the zebrafish. These small fish, which grow to the length of a little finger, helped her and collaborator Professor Paul Edelstein from the University of Pennsylvania (currently on sabbatical in Cambridge) to make an important discovery that could explain why it takes a six month course of antibiotics to rid the body of the disease, rather than seven to ten days that most infections take – and yet, in the lab can easily be killed.
Within our bodies, we have a host of specialist immune cells that fight infection. One of these is the macrophage (Greek for ‘big eater’). This cell engulfs the TB bacterium and tries to break it down. This, together with powerful antibiotics, should make eliminating TB from the body a cinch. Prof Ramakrishnan’s breakthrough was to show why this wasn’t the case: once inside the macrophages, TB switches on pumps, known as ‘efflux pumps’. Anything that we throw at it, it just pumps back out again.
“Once we’d identified the pumps, we started to look for drugs that are out there in the market and tested a few of them,” she explains. “We found that verapamil, an old drug, made the bacteria susceptible to two of the antibiotics we use to fight TB.”
The trial due to start soon of verapamil, which is commonly used to treat high blood pressure, will take place at the National Institute for Research in Tuberculosis (NIRT) in Chennai, India. Prof Ramakrishnan is one of a number of brilliant minds working as part of a collaboration between the NIRT and the University of Cambridge to apply the very latest in scientific thinking and technology to the problem of TB.
An expansion of this collaboration has now become possible through the recent award of a £2 million joint grant from the UK Medical Research Council (MRC) and the Department of Biotechnology (DBT) in India. Yet even if the Chennai venture is successful, and research from the partnership leads to a revolution in how we understand and treat TB, the research teams involved recognise that this is unlikely to be enough to eradicate the disease for good.
“TB is as much a public health issue as one of infectious diseases,” says Ramakrishnan, pointing to Europe, where even before the introduction of antibiotics, the disease was already on the decline. “We need better nutrition, better air, less smoking, reductions in diabetes.”