UP academics’ work on African mole rat research could pave way for new painkillers for humans

Three University of Pretoria (UP) scientists are part of a team whose research on African mole rats has led to a discovery that may hold the key to pain management in humans.

The research team was led by Professor Gary Lewin, group leader of the Max Delbrück Centre for Molecular Medicine (MDC), Berlin, Germany, US neuroscientist Professor Thom Park and University of Pretoria zoologist Professor Nigel Bennett, supported by UP colleagues Dr Heike Lutermann and Mr Daniel Hart.

The team’s research into African mole rats, which are indigenous to the sub-Saharan region, led to the discovery that these rodents are insensitive to many different types of pain. This species’ adaptations to extreme environment (a lack of oxygen and a surplus of carbon dioxide underground, as well as a humidity close to saturation) could hold the key to further advances in human pain management.

Their unique findings are published in the latest issue of the prestigious American research journal Science.

According to Prof Bennett, the research “has revealed that as a consequence of genetic changes to its pain channels, the highveld mole rat, which is found in South Africa’s Gauteng province, is able to live alongside venomous ants with painful stings that mole rats avoid.”

He explained that about ten years ago, Prof Lewin’s group, which investigated the unusual sensory world of the naked mole rat, revealed that these burrowing rodents were remarkably resistant to pain when exposed to acid or capsaicin – the substance that gives chilli peppers their heat (PLoS Biology).

However, in their latest study, the UP researchers, along with colleagues from the Sokoine University of Agriculture and University of Dar es Salaam in Tanzania, investigated the extraordinary insensitivity to pain in other African mole rats. Prof Bennett explained that, “The research team explored how eight other African mole rat species related to the naked mole rat respond to three substances that usually cause a brief burning sensation on the skin of human beings and other mammals. Those substances were: diluted hydrochloric acid, capsaicin, and allyl isothiocyanate (AICT). AICT is what gives wasabi, the condiment served with sushi, an extremely hot taste. The idea was that mole rats are naturally exposed to these and similar substances in the wild. These behavioural experiments were performed at the University of Pretoria with Prof Lewin and his postdoctoral students.”

The study revealed that three mole rat species proved to be insensitive to acid. Two species did not show evidence of pain after having a capsaicin solution injected into their paw.

Furthermore, only a single mole rat species – the highveld mole rat – proved to be unaffected by AICT. “AICT attacks amino acids in the body and can thus destroy proteins. That is why all the other species we know avoid coming into contact with the substance. The highveld mole rat is the only species in the experiment that had no problem with AICT, while phylogenetically very closely related species showed a response to AICT,” Prof Bennett said. “The researchers at MDC took sensory tissue from the spinal cord and spinal ganglions of all nine species studied. Through the use of state-of-the-art DNA sequencing technology, Prof Lewin and his group were able to compare the activity of around 7 000 genes inside that tissue.”

Relatively quickly, the MDC group observed that the activity of two genes were altered within the animals that felt no pain. These genes contain the blueprint for the ion channels TRPA1 and NaV1.7. “Interestingly, it is already known that these two channels are involved in the perception of pain,” Prof Bennett said.

AICT and many other irritants found in roots – one of the mole rat’s main food sources – activate TRPA1. This is why, over the course of evolution, many species have downregulated the gene for this channel. The ‘wasabi channel’ is the only one to be completely switched off in the highveld mole rat. “Prof Lewin went on to discover that this is down to a particularly active gene for another channel – the constitutively open channel NALCN, known as a ‘leak channel’,” Prof Bennett said. “The research group found that the expression of this channel was the only one that was significantly altered in the highveld mole rat.”

During the course of evolution, the highveld mole rat has clearly acquired an altered gene for a single ion channel, which has allowed it to make its home in places that are avoided by other species of mole rat. “This discovery is yet another mind-blowing example of how environment shapes evolution over the longer term, and could lead to the development of highly effective painkillers for humans. The highveld mole rat has showed us that high expression of the NALCN channel seems to be a very effective way of alleviating pain.”

Irritants that may penetrate the skin such as insect stings (bees, wasps, hornets and ants, which can bring about anaphylactic shock) and various nettles and other plant hairs that carry irritants which bring about pain could potentially be alleviated in future by the administration of chemicals that alter the movement of ions through membranes. “This could help ease pain and potentially save lives,” Prof Bennett said. “But this is another project for the future!”

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Researchers

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  Professor Nigel Bennett

  Professor Nigel Bennett has been at the University of Pretoria (UP) for 26 years. He holds a BSc (Hons) in Zoology, which he obtained at Bristol University in the UK, and undertook his PhD studies at the University of Cape Town.
  
  His research focus is animal physiology and behaviour using the African mole rat as his model animal. His work is directed primarily at studying the social regulation of reproduction in mole rats.
  
  Prof Bennett’s research record ranks him among the best researchers studying social regulation of reproduction in any group of mammals in the world. He has investigated cooperative breeding in mammals from a variety of perspectives. This multi-faceted approach has led to an integrated understanding of reproductive suppression in mole rats of a type that has not been achieved for any other taxa. His research has set the benchmark for our understanding of phylogenetic and ecological constraints that regulate reproductive success and social evolution in mammalian species.
  Prof Bennett has always been interested in why some organisms adopt a social lifestyle and others do not. As a young boy, he was fascinated by how wood ants worked for the common good of a queen. His interest in mole rats came about while he was an undergraduate at Bristol University, after he had read a seminal paper by scientist Jennifer Jarvis on cooperative breeding in the naked mole rat. Upon obtaining a position as a doctoral candidate, Prof Bennett wanted to see if this was a feature common to other African mole rats. He went on to study the Damaraland mole rat, and found it to have incredible social organisation similar to that of social insects and termites.
  
  Prof Bennett is now the world leader in African mole rat biology, particularly in reproductive physiology. A research milestone for him was discovering that breeding female naked mole rats orchestrate non-breeding males and females in the colony to exhibit high prolactin levels. This inhibits the release of hormones that stimulate the development of reproductive activities in the gonads, as evidenced by a lack of follicular development in ovaries and a reduction in numbers and motile sperm in testes. Prolactin also results in individuals exhibiting helping behaviour and cooperative care of the young.
  
  After nearly three decades of research on the reproduction of social African mole rats, Prof Bennett has not been able to determine how the breeding female actually inhibits reproduction in physiologically suppressed animals. This would be the magic bullet for potential contraception in humans.
  He leads a research group that strives to unravel how social evolution arose in African mole rats – solving this puzzle has important implications as to how social evolution arose among hominids. Essentially, it comes down to food acquisition and protection from predators, which is a central theme in social evolution in most mammalian groups.
  
  Two people influenced his career: Prof Brian Follett – who supervised Prof Bennett’s honours project and whose infectious enthusiasm for science and incredible lectures fired up Prof Bennett’s imagination – and Prof Jennifer Jarvis, who drove his passion to work on mole rats.
  
  In 2021, Prof Bennett was made an honorary member of the American Society of Mammalogists, a title bestowed on fewer than 100 luminaries in a century. He has been a visiting professor at the School of Chemical and Biological Sciences at the University of London’s Queen Mary College since 2005. More recently, he was a visiting professor at the Department of Zoology at King Saud University in Saudi Arabia.
  
  He is a member of the Academy of Science of South Africa, and a fellow of the Zoological Society of London, the Royal Society of South Africa and the African Academy of Sciences.
  
  Prof Bennett was awarded the UP Chancellor’s Medal for his research on three occasions and has received the Exceptional Academic Achiever Award for the past 14 years. He was also the recipient of the Zoological Society of Southern Africa’s gold medal and received the Havenga Prize for outstanding contributions to Life Sciences, awarded by the Academy of Science and Arts of South Africa. UP awarded him the University of Pretoria Commemorative Research Medal for being one of the top 100 scientists in 100 years of its existence.
  
  Prof Bennett has served as president of the Zoological Community of Southern Africa for two years. He is also editor-in-chief of the Journal of Zoology and a past editor of Proceedings of the Royal Society B: Biological Sciences. In 2013, he was the handling editor of Biology Letters, another Royal Society of London journal. He has published 433 papers in international peer-reviewed scientific journals, co-authored a specialist book published by Cambridge University Press and has penned 15 chapters in books.
  
  In his spare time, Prof Bennett travels to different countries in Africa to explore the wildlife. He particularly enjoys visiting the mountain gorillas in Rwanda and Uganda, and the eastern lowland gorillas of the Democratic Republic of the Congo. He is also an avid collector of African art and frequently visits markets to add to his collection.
  
  If he were not a researcher, Prof Bennett would have liked to have been a game warden in one of East Africa’s national parks to contribute to the protection of the incredible African fauna from poaching.
  
  ORCID ID: 0000-0001-9748-2947
  

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  Dr Daniel Hart

  Dr Daniel Hart is a postdoctoral fellow at the University of Pretoria. His research focuses on the evolutionary physiological and biomedical studies of African vertebrates.
  
  Dr Daniel Hart was part of an international team with Prof Nigel Bennett whose research into African mole-rats was not only published in the distinguished journal Science but made the cover.
  
  Prof Nigel Bennett, a professor in UP’s Department of Zoology and Entomology, and post-doctoral fellow Dr Daniel Hart worked closely with the Max Delbrück Center for Molecular Medicine in Berlin, Germany on their recent research, the findings of which show that mole-rats communicate in their own dialect.
  
  He tells us more about their groundbreaking research.
  
  What makes African mole-rats so interesting?
  DH: They are great models to show how animals adapt to their environment. For example, their broad spectrum of sociality has been brought about by the different species inhabiting different climatic regions. Simultaneously, their incredible ability to withstand hypoxic (low oxygen) conditions has come about because of their exclusive subterranean lifestyle.
  
  What made you focus your research on them?
  DH: When I began my research career, a wise mentor gave me a piece of advice: study animals that you can ask interesting questions about. So far, I have not found an animal that you can ask more interesting questions about than African mole-rats ­­– the number of exciting questions and answers that mole-rats have to offer drew me to studying them.
  
  How does their social and communication habits have an impact on how we understand them?
  
  DH: Naked mole-rats live in large families (50 to 60 individuals), with some colonies reaching 300, controlled by one female, the queen. Each colony member has its own “job”, and everyone recognises their own colony and family members, even in the dark. Even after the vast number of studies on these amazing animals, how the colony structure is maintained has somewhat eluded us. But, like humans, it may come down to dialects to some extent. From this study, we have learnt that each mole-rat colony has its own dialect, dictated by the queen, allowing colony cohesion and detection of intruders. Interestingly, this dialect can be learnt, which is an uncommon ability in most animals. This new understanding brings us closer to figuring out how these large families work together and stay together. This understanding can possibly help us in furthering our knowledge about human dialects.
  
  Are there any other animals that provide as interesting an array of applications as the mole-rat?
  
  DH: We are fortunate, as Africa has a treasure trove of unique animals with remarkable features and abilities. One such animal we are working on is the tenrec, which is a fantastic model of a prehistoric mammal. With these animals, we hope to peer back in time to unravel essential questions about evolution. Like the mole-rats, they also possess remarkable physiological and molecular traits, which could be vital to biomedical studies.
  
  What do you do in your spare time?
  DH: I have quite a big interest in other scientific subjects, namely astrophysics, astronomy and cosmology. I also enjoy listening to books or podcasts on these subjects and reading articles when I get a chance. Also, I am passionate about sport, so I enjoy catching up on the world’s sporting events when I can.

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  UP academics’ work on African mole rat research could pave way for new painkillers for humans