Human whipworm (Trichuris trichiura), the parasite responsible for trichuriasis, a neglected tropical disease. Image Credit: AdobeStock
Genomics has huge potential to improve our understanding of the fundamental biology of neglected tropical diseases (NTDs) and provide actionable information to aid in their control. On World NTD Day 2023, we consider how Wellcome Sanger Institute scientists and their collaborators are using genomic technologies to attend to some of these diseases, with a view to empowering elimination efforts.
Neglected Tropical Diseases (NTDs) disproportionately affect people living in tropical and sub-tropical regions of Sub-Saharan Africa, South America and Asia. Caused by parasitic worms, protozoa, viruses, fungi, and bacteria, not only are they a result of poverty, but also contribute to the cycle of poverty, with a high disease burden impacting healthcare services and depressing economic productivity. The World Health Organisation (WHO) recognises 19 infectious diseases as being NTDs, including dengue and chikungunya, Guinea-worm disease, human African trypanosomiasis (or sleeping sickness), onchocerciasis (or river blindness) and trachoma. Collectively, these 19 diseases affect nearly two billion people, including 500 million children, and cause around 200,000 deaths a year globally.
Despite the high burden, NTDs do not receive attention or research funding commensurate with their impact. Diseases such as malaria, HIV and tuberculosis, which cause a high level of disease in much of the world, rightly receive high levels of funding. However, much of the money spent studying other infectious agents and developing new drugs to treat them is focused on diseases that also have a significant burden in Europe and North America. Unfortunately, this leaves a funding gap for a great swathe of diseases that largely affect only tropical regions. In turn, this means that the NTD field attracts fewer researchers, making progress toward understanding their biology and developing new ways to control NTDs slow by comparison to more high-profile pathogens.
For example, Dr Mat Beale works with clinicians and scientists around the world on Yaws disease, a bacterial infection caused by Treponema pallidum subspecies pertenue, which causes disfiguring and stigmatising skin lesions, mostly in children. While over 7 million SARS-CoV-2 genomes, approximately 1.5 million Mycobacterium tuberculosis genomes, and more than 60,000 HIV genomes have been sequenced and shared, fewer than 30 genomes are available for T. pallidum subsp. pertenue, and many of those come from a single study in Papua New Guinea. As noted by Mat, “This means that our understanding of the genetic diversity of T. pallidum, of how different genetic ‘types’ are distributed around the world, and of how individuals become infected is extremely limited.”
Where genomics adds value
The increasing accessibility and decreasing costs of genomics over the past twenty years have enabled scientists at Sanger, and elsewhere, to generate draft and reference genomes for the pathogens behind many neglected tropical diseases. These genomes help to provide the foundations on which researchers around the world investigate the fundamental biology of these neglected diseases. For example, Dr Matt Berriman and his team developed foundational genomic datasets for a wide range of NTDs, including the parasites behind leishmaniasis and sleeping sickness, as well as a range of helminths. The team have used comparative analyses to provide some of the earliest insights into the genetic basis for many aspects of parasite lifecycle and pathogenesis.
However, ongoing efforts to sequence many more genomes are needed to understand how these pathogens evolve and spread through human populations over time, and how they respond to interventions. Such ‘genomic epidemiology’ allows scientists and public health workers to track the emergence of new infections after a population has been treated during mass drug administration (MDA) programmes. In the case of Yaws in Papua New Guinea, genomics allowed Mat and his colleagues to determine that new cases were the result of multiple untreated infections, which informed strategies to increase the proportion of the population treated during subsequent MDA programmes.
Genomic epidemiology can also help to understand the emergence and spread of drug resistance in the pathogens causing NTDs. Together with collaborators across Africa and Europe, Dr Stephen Doyle works on the genomics of soil-transmitted helminths, a group of parasitic nematodes that infect over a billion people worldwide each year. As with Yaws, efforts to control soil-transmitted helminths primarily rely on MDA programmes, which carry the risk of selecting for the evolution of drug resistance. Stephen and his colleagues use genomics together with measurements of drug responses to understand how populations of parasites are connected and to look for evidence of resistance emerging. Being able to distinguish how often resistance arises, and how it then spreads through a population can help to refine control efforts in terms of where treatment campaigns should be conducted, and which drug combinations might minimise the risk of resistance evolving.
"The genomes of these parasitic worms hold clues as to how they have become successful in the past and how they will evolve in the future. Genomics has significant potential to unlock this information and provide real benefit towards strategies that aim to control these diseases as a public health problem.“
Stephen Doyle, Parasites and Microbes programme, Wellcome Sanger Institute
NTDs disproportionately affect people in tropical and sub-tropical regions.
While large-scale whole genome sequencing has the potential to grow our knowledge about NTD biology and inform control efforts, for most of these diseases, we still lack real-world proof-of-principle studies to demonstrate how genomic data can add value to existing control efforts. The global genomic surveillance of SARS-CoV-2 seen during the pandemic may now help to provide impetus to undertake such studies. Awareness of the potential benefits of large-scale genomic surveillance is now far greater among funders and policymakers, which can be capitalised upon to boost the genomics of NTDs.
More attention and money will certainly help, but there are many other challenges to be overcome if NTD genomics is to catch up with better-studied pathogens. Both Mat and Stephen highlight access to samples as a primary challenge for the field. Access is hampered by a lack of active surveillance or collection of samples as part of existing clinical studies or public health campaigns. It is also restricted by the difficulties in recovering DNA from samples to sequence. For Yaws, swabs of skin lesions yield low levels of DNA for sequencing, and that which is present is a mixture of DNA from humans and a whole range of skin-dwelling microbes, meaning that less than 1 per cent of it comes from Treponema pallidum. Mat and his colleagues use a special technique to ‘enrich’ Treponema DNA, however, this technique is expensive and difficult to perform, requiring specialist expertise and equipment not found in most sequencing laboratories. The picture is similar for soil-transmitted helminths, whose eggs are sampled from faeces which is densely packed with other microbes, while the eggs can be tough to crack open to access the DNA. Furthermore, people are often infected with more than one species of helminth, so obtaining sufficient DNA can be challenging.
In addition, there are often legal and regulatory issues that can complicate genomic surveillance efforts. International agreements about sharing of samples between countries, such as the Nagoya Protocol, are quite rightly in place to ensure equitable sharing of benefits arising from the use of genetic resources and support the conservation of biodiversity. However, such agreements also add a degree of complexity that can delay or prevent vital infectious disease research. Increasing sequencing capacity in endemic countries can help to address this issue, although, at present, limitations in terms of facilities, adequate reagent supply chains and expertise in genomics and bioinformatics often make it more cost-effective to sequence at institutes like Sanger, despite the additional logistical challenges associated with transporting samples around the world.
Stopping the neglect
Supporting partners in establishing or expanding their sequencing capacity and helping to train a new generation of genomic scientists and bioinformaticians is going to be key to using these technologies to tackle NTDs. However, the market forces that have led these diseases to be neglected up to now are not simply going to evaporate overnight. As such, perhaps it is worth reframing the building of genomic capabilities in the NTD field as part of the insurance policy that wealthy nations now realise must be invested in to prepare for, and prevent, the catastrophic impact of future global pandemics. Adoption of genomics proliferated during COVID-19 and building on this by further training and resourcing scientists to be capable of ongoing genomic surveillance of endemic neglected diseases will not only benefit efforts to study and control those diseases, but will provide a highly trained workforce that could be rapidly redeployed to track and study future emerging pandemic threats as part of a resilient healthcare system.
With continued hard work and commitment by individuals and organisations worldwide committed to NTD control, and a bit of luck, some of these diseases will hopefully not only stop being neglected but rather become eliminated as a public health problem in the coming years. Genomics will have an important role in realising this vision.