A-rating for TB researcher
Tuberculosis (TB) researcher and distinguished professor Robin (Rob) Warren was never an A-symbol scholar at school, and even struggled academically at times. Yet, after studying biochemistry, he found his purpose in research – so much so that, in 2022, the National Research Foundation (NRF) awarded him an A1-rating, recognising him as a world leader in research on strains of Mycobacterium tuberculosis, the bacterium that causes TB.
Warren’s research has continuously challenged dogma about recurrent TB, how to identify outbreaks, and the standard of care provided to patients.
Since 2017, Warren has served as unit director of the South African Medical Research Council’s (SAMRC) Centre for Tuberculosis Research, housed within the Division of Molecular Biology and Human Genetics in the Faculty of Medicine and Health Sciences at Stellenbosch University (SU). He is a core member of the DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research and heads the TB Genomics Research Group.
In 2015, he received the SAMRC Gold Medal for scientific excellence; in 2018, a SU Chancellor’s Award; and over the past decade, six SU Rector’s Awards.
His team was the first to suggest that multidrug resistant TB (MDR-TB) is endemic to South Africa. They highlighted the worrying emergence of even more resistant strains: so-called ‘extensive drug-resistant TB’ (XDR-TB) and ‘totally drug-resistant TB’ (TDR-TB) – strains of the bacterium that are resistant to all available anti-TB drugs.
Warren has demonstrated that patients may be infected with multiple different strains of Mycobacterium tuberculosis, and has mapped the pathways whereby these strains become resistant to most standard TB antibiotics – or worse, to the new drugs used to treat drug-resistant TB.
Becoming a TB expert
Prof Paul van Helden was Warren’s predecessor as the unit director of the SAMRC Centre for Tuberculosis Research. In 1994, he introduced Warren to TB research when he appointed him as a postdoctoral researcher, despite the young scientist being hours late for the job interview.
As Warren remembers it, he felt he couldn’t just leave the intricate electron microscopy experiment that he was busy with and waste the opportunity to get an exciting result, simply to be on time.
“Paul wasn’t miffed at all. The reason I gave for being late might just have made a good impression. I don’t really know,” he muses.
Back then, this fullblood Capetonian was in the final throes of his PhD in biochemistry at the University of Cape Town. He was studying active chromatin extracted from sea urchin embryos.
When asked why he took 11 years to complete his PhD, Warren is quite wistful, even thankful: “My mentor at the time, Prof Claus van Holt, let me do all sorts of other things besides my PhD. It was wonderful. Through this journey, I gained experience and skills.
“It set me up well for when I arrived at Stellenbosch University.”
His first TB-related assignment focused on molecular epidemiology. Warren had to genetically ‘fingerprint’ Mycobacterium tuberculosis to find different strains in samples collected across South Africa.
“It was like doing the bacterium’s ‘paternity test’: Who infected who?”
Hundreds of different strains were identified, many more than researchers could ever have guessed. Today, the archive of clinical TB isolates Warren started in 1995 houses over 60 000 drug-susceptible and drug-resistant isolates.
“The Centre’s culture bank represents the largest collection of clinical strains cultured from TB patients in the developing world. It’s a national and international resource,” says Warren, who is something of an honorary historian on how TB strains have evolved and spread throughout the country.
His first paper on TB strains was published in 1996 in the South African Medical Journal. Some 370 publications have followed, along with 15 book chapters and 6 patents. As supervisor and co-supervisor, he has helped 57 postgraduate students earn their degrees.
Warren’s research group collaborates broadly and contributes to the World Health Organization’s (WHO’s) guidelines on TB diagnostics. They have provided mounds of information on the genetics of Mycobacterium tuberculosis to global initiatives by analysing the bacterium’s genome in detail, using state-of-the-art whole genome sequencing techniques.
Treating without knowing
Warren is nearing retirement age, but still has the proverbial whiteboard full of questions he wants to answer through current and future projects, all in an effort to inform policies.
He believes it should be possible to design an app that diagnoses TB when someone coughs. He dreams of having armies of mobile clinics or the likes across cities and towns to provide patients with easier and more humane treatment.
Warren also wants to know how repeat infections impact the lungs of TB patients. He worries about how the disease spreads when people come together to drink or use inhaled drugs, or within the confines of prisons.
“My research continues to show that transmission drives the drug-resistant TB epidemic. These findings have important implications for TB control. They demonstrate that infectious cases are not diagnosed timeously.”
Moreover, his recent research showed that the XDR-TB epidemic is perpetuated when infectious patients return to their communities after hearing that their treatment is unsuccessful.
“We’ve known since the 1990s that treatment outcomes for people living with drug-resistant TB really aren’t great. Those strains are now endemic and are systematically acquiring additional resistance.
Warren is already worried that resistance to bedaquiline – the first new drug against MDR-TB in 40 years – might soon be on the cards if it is not prescribed with extreme caution.
“Doctors often treat without knowing. We could land up losing our newest drug. If we don’t test for resistance and understand why it develops, we could have further drug resistance.”
Nowadays, genetic tests can personalise treatment before it commences. It pinpoints which TB antibiotics will work for which patient, depending on the strains found in their lungs.
As such, Warren would like to see genetic tests become part of routine TB testing, and is pinning hope on the roll-out of a next-generation sequencing project in collaboration with the National Health Laboratory Service and international partners.
His team and the US-based non-profit Translational Genomics Research group is collaborating to identify so-called ‘heteroresistant TB clones’. TB heteroresistance entails the coexistence of both a susceptible and a resistant strain in a patients’ lungs – a situation that makes providing adequate treatment exceedingly difficult. The researchers are developing more sensitive targeted deep sequencing (TDS) approaches to sequence the genomic regions of strains hundreds of times. This is done to timeously diagnose heteroresistance and so improve treatment outcomes.
The makeup of a researcher
Warren believes it is his personal makeup, not necessarily his topic of research, that makes him a dedicated scientist.
“I love my job. I get up in the morning to come to work,” notes this avid gardener, handyman and family man.
“Being a good researcher means you cannot stop thinking. There’s always that something that ticks at the back of my mind, and often wakes me in the middle of the night.”
Key collaborations with colleagues worldwide have been crucial to his research success. His new ideas develop best through a constant “banter between people”, he says.
His advice to younger researchers is simple: “Try to think as much as possible, and then enjoy what you are doing. If it’s a bind, you won’t be able to think.”
Prof Robin Warren
Photo by Stefan Els
Written by Engela Duvenage