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To the Crick! Part 5: 100 years of tuberculosis research and 70,000 years of evolution

For our final post in the ‘To the Crick’ series, we hear from Luiz Pedro Carvalho. He’s moving from the site of what was the National Institute of Medical Research (NIMR) in Mill Hill to the new Francis Crick Institute building in King’s Cross. We find out about Luiz’s work, focused on tuberculosis (TB), and look back at over 100 years of MRC-funded TB research.

a side view of open-plan lab space inside the Crick

Open-plan lab spaces inside the Crick

“It’s a mixture of excitement and already missing the place,” says Luiz. Mill Hill was home to NIMR for most of its lifetime but activities there have nearly come to an end. The venerable institute is now part of the Francis Crick Institute.

MRC’s long history of TB research

The poster reads: "The dawn of hope: National insurance against sickness and disablement"

A poster on National Insurance published by the Liberal Party in 1911

At the MRC we have been funding work to understand and treat tuberculosis (TB) since we began. At its very first meeting, back in 1913, the fledgling Medical Research Committee discussed a new national scheme for health insurance that would treat and study TB.

Later on, researchers at Mill Hill pioneered randomised controlled trial design while testing patulin – a fungal toxin – to treat the common cold, and then streptomycin to treat pulmonary TB. They developed a system that meant that neither the patient nor the clinician knew whether the drug or a placebo was being used.

The gold standards of clinical trial design that we use today are based on that work. In 2009, former MRC Chief Executive Professor Colin Blakemore spoke to the researcher who led the streptomycin trial, John Crofton, about the importance of randomisation and blinding in clinical trials.

The global terror of TB

Although now far less common in the UK than in the past, TB is a huge and tenacious global problem. Around a third of the world’s population is infected and the disease kills 1.5 million people every year.

“In my group we’re trying to understand and map exactly how the bacteria that cause TB, Mycobacterium tuberculosis, work in humans, says Luiz.

Tuberculosis researcher Luiz stands in a new, but still empty, lab

Luiz Carvalho is his brand new lab at the Crick

“The number of people who have an infection we can’t treat is growing all the time,” Luiz explains. “That’s because the strain of bacteria they’re infected with is resistant to all the drugs we have available. We need new drugs but we are struggling to keep up with the speed at which bacteria develop resistance. We need to understand TB better so that, perhaps, we can find completely new ways to treat it.”

Recently, research in West Africa, led by MRC Unit The Gambia, showed the problem of multi-drug resistance was worse than previously thought. They found that six per cent of people infected with TB for the first time, and 35 per cent of people who had been infected before, had a multi-drug resistant strain. These statistics are much higher than previous WHO estimates of two and 17 per cent.

“Over the last 70,000 years, M. tuberculosis has evolved to be completely at home in humans,” says Luiz. “We are their favourite source of nutrients. Why does living in humans work so well for these bacteria? How does each individual bacterial enzyme do its job? And how do those processes relate to survival, disease and resistance to antibiotics?”

Metabolomics

Exploring all of these questions requires a range of approaches: “We use quite a bit of genetics, biochemistry, bioinformatics, structural biology… but the key technique that we use is something called ‘metabolomics’,” explains Luiz.

‘Metabolomics’ involves separating out all of the molecules that make up a cell, fluid or tissue, allowing you to identify them.

Archer Martin in his lab

Archer Martin was working at Mill Hill when he won the 1952 Nobel Prize jointly with Richard Synge. The cigarette in the lab seems utterly out of place now. Perhaps because four years later, two other MRC researchers, Sir Richard Doll and Sir Austin Bradford Hill, showed that smoking causes cancer.

“Once you know what everything is, you can start to understand how it works. We make small alterations to the system, such as adding a drug or deleting a gene, and get a clear snapshot of what’s happening inside the individual bacterium.”

“To do metabolomics experiments we’re very keen on a technique called a liquid chromatography–mass spectrometry. Liquid chromatography is the method that we use to separate, identify and quantify the molecules. The method was invented in Mill Hill back in the 1950s. Archer Martin and Richard Synge got a Nobel Prize in Chemistry for it. Then we use mass spectrometry to be able to quantify levels of hundreds of metabolites at the same time.”

Interdisciplinary research and collaboration

“Our lab has a very diverse skillset. We have biochemists and chemists, computational and structural biologists, and geneticists and microbiologists. So everyone has a different language. It can be very hard to communicate at times, but we try our best!


Hear Luiz discussing the joys and challenges of interdisciplinary research in our podcast 

“We also collaborate significantly with people from outside. We have collaborations in physics, maths and chemistry. We also work with people who can access clinical strains of TB, rather than strains cultivated in the lab.  That keeps us in touch with how the disease is changing and developing in patients.

“One of the great things about the Crick building is that we now have ventilated fume hoods – designed to protect the user from toxic fumes – so chemistry groups can come and work with us.  It’s really exciting to actually have collaborators coming in to the building and making molecules and trying to help us identify enzymes, pathways, drugs.

“At Mill Hill we had to send an email, schedule a meeting, go to another site…  But now these people are going to be here in the fifth floor! We just have to pop in the lift and discuss what the issue is and how we can solve it.  That can really accelerate the research we’re doing.”

Find out more

See inside the Crick in our photo album.

Find out more about MRC history in our timeline.

Find out more about Luiz on the Crick website.

You may be interested in previous articles in this series:


Also published on Medium.

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