Hepatitis B virus (HBV) infection is a leading cause of chronic liver diseases, that spreads among individuals through blood or body fluids. According to the World Health Organization, globally 1.2 million new HBV infections are reported every year – most in low- and middle-income countries. HBV infections are limited to a few species, including humans and chimpanzees. Despite their close evolutionary relationship with these animals, old-world monkeys are not susceptible to HBV infections.
In a new study published in Nature Communications, scientists led by Visiting Professor Koichi Watashi from the Tokyo University of Science to uncover why monkeys are naturally resistant to HBV infection.
Using cryo-electron microscopy, scientists solved the structure of a membrane receptor found in liver cells called the sodium taurocholate co-transporting polypeptide (NTCP) in macaques. HBV binds to human NTCP using its preS1 region in the surface protein. Prof Watashi explains, “We identified a binding mode for NTCP-preS1 where two functional sites are involved in human NTCP (hNTCP). In contrast, macaque NTCP (mNTCP) loses both binding functions due to steric hindrance and instability in the preS1 binding state.”
To understand this ‘interspecies barrier’ against viral transmission, Prof Watashi and his team compared the structures of hNTCP and mNTCP, identifying differences in amino acid residues critical for HBV binding and entry into liver cells. hNTCP and mNTCP share 96% amino acid homology, with 14 amino acids distinct between the two receptors. A key distinction among these differences is the bulky side chain of arginine at position 158 in mNTCP, which prevents deep preS1 insertion into the NTCP bile acid pocket. For successful viral entry into liver cells, a smaller amino acid like glycine, as found in hNTCP, is necessary.
Interestingly, the substitution of Glycine by Arginine in mNTCP was at a position far away from the binding site for bile acid. Prof Watashi adds, “These animals probably evolved to acquire escape mechanisms from HBV infections without altering their bile acid transport capacity. Consistently, phylogenetic analysis showed strong positive selection at position 158 of NTCP, probably due to pressure from HBV. Such molecular evolution driven to escape virus infection has been reported for other virus receptors.” Further lab experiments and simulations revealed that an amino acid at position 86 is also critical for stabilising NTCP’s bound state with HBV’s preS1 domain. Non-susceptible species lack lysine at this position, which has a large side chain; macaques instead have asparagine, which contributes to HBV resistance.
The researchers also noted that bile acids and HBV’s preS1 competed to bind to NTCP, where the long tail-chain structure of the bile acid inhibited the binding of preS1. Commenting on these findings, Prof Watashi stated, “Bile acids with long conjugated chains exhibited anti-HBV potency. Development of bile acid-based anti-HBV compounds is underway and our results will be useful for the design of such anti-HBV entry inhibitors.”
By unravelling the structure of mNTCP and pinpointing the amino acids that facilitate viral entry into liver cells, researchers have opened the door to new therapeutic avenues. Furthermore, the implications extend beyond HBV, offering critical insights into other viruses, including SARS-CoV-2, and their potential to cross species barriers. This research not only enhances our understanding of viral dynamics but also serves as a crucial tool in the ongoing quest to predict and prevent future pandemics.
The future of global health hinges on these revelations, promising a path toward more equitable access to treatments and a stronger defence against emerging viral threats.
Nomantu Nkomo-Ralehoko is the MEC for Health and Wellness in Gauteng. (Photo: GautengHealth/X)
Several opposition politicians and commentators have flagged what appears to be chronic leadership problems at the Gauteng Department of Health.
Criticism of leadership and governance at the Gauteng Department of Health (GDOH) is amping up as the department repeatedly makes headlines for questionable appointments. This unfolds alongside a damning auditor-general report, all while hospitals and clinics across the province grapple with ongoing challenges.
Arguably, the most controversial appointment is that of Arnold Malotana. He was quietly named head of department shortly after the May 29 national elections, following a year of serving in an acting capacity. Malotana has been with the department in various positions since 2008, according to his LinkedIn profile.
SIU investigation
Malotana has been implicated in a case being investigated by the Special Investigating Unit (SIU). It relates to the alleged manipulation of supply chain processes in 2016 and 2017 in favour of a company called BAS Medxpress (BAS Med). It has been alleged that Malotana and two senior officials – Edgar Motha and Sheriff Lecholo – took bribes to the tune of R8 million. The case made headlines a year and a half ago when amaBhungane lifted the lid on an affidavit from a whistleblower, who himself was part of the alleged tender-rigging scheme. The SIU investigation was however only ordered by presidential proclamation this November. According to amaBhungane’s reporting last year, all those implicated in the matter have denied wrong-doing.
SIU spokesperson Kaizer Kganyago said the probe will focus on two supply contracts – one for plastic containers and another for orthopaedic instruments – to determine if any actions broke laws, policies, or Treasury or health department rules, and whether they may be fraudulent.
“Such conduct may include manipulation of the department’s supply chain management processes by service providers, suppliers, officials, or other third parties, often in collusion with departmental employees or those in entities under its control, to secure undue benefits for themselves or others. This can result in unauthorised, irregular, or fruitless and wasteful expenditure incurred by the department, its entities or the State,” he said in a statement.
Questions over qualifications
Malotana has also been under separate investigation regarding his qualifications when his appointment as head of department was made. His LinkedIn profile lists his education as two years (2013 – 2014) at the Durban Institute of Technology and a master’s degree in public management from Regenesys Business School, with no dates provided.
Earlier this year, Jack Bloom, a DA member in the provincial legislature, wrote to the Public Protector to ask that they investigate Malotana’s appointment. Public Protector passed the matter to Parliament’s Portfolio Committee for Public Service and Administration. In turn, the committee chair requested the Public Service Commission (PSC) to investigate.
In mid-November, the PSC “reportedly” cleared Malotana on the allegations relating to his qualifications and appointment. The PSC report was leaked to The Star newspaper with the complainants – the DA – as well as the portfolio committee chairperson not yet having had sight of the report. Spotlight also hasn’t yet been able to access a copy.
According to The Star, the PSC found that a master’s degree was not explicitly listed as a required qualification, and as a result, the commission found that Malotana did meet the requirements.
Bloom told Spotlight: “It’s highly irregular that the PSC report is leaked to a specific newspaper.”
Meanwhile, the SIU investigation continues, and the DA has reiterated its call for Gauteng Premier Panyaza Lesufi to remove Malotana from his post. Heads of departments are appointed by provincial premiers.
The Office of the Premier did not answer Spotlight’s questions about Malotana or the SIU investigation. However, according to a statement from the DA, Lesufi said in a Gauteng Legislature meeting last week that he would wait for the SIU investigation to be completed before taking any action against Malotana.
Millions spent on suspended staff
In September, responses to questions posed by Bloom in the Gauteng Legislature revealed that the provincial health department spent over R13 million on salaries for nine suspended staffers in recent years. Among these were Advocate Mpelegeng Lebeloane, former chief director of legal services, who received R4.7 million while on suspension from July 2019 until 2023. He was later reinstated and then retired in July 2024.
Bloom said in a statement at the time: “Three senior staff were suspended since 26 January 2022 for alleged financial misconduct concerning the refurbishment of the Anglo Ashanti Hospital. One has recently resigned, but more than R6 million has been spent so far on their salaries in this inexcusably long-running matter.”
The other staff members had been suspended on a range of charges, including sexual assault, assault and a job-selling scam.
Bloom said the long delays in concluding disciplinary processes smacked of a failure of accountability and were a drain on taxpayers’ monies and resources.
Spotlight put questions to the health department about its mechanisms and processes to ensure efficient and appropriate disciplinary action. The department’s spokesperson Motalatale Modiba said the cases in question “cut across various departments”. He added: “The employees were suspended with full pay and the delays mainly had to do with ongoing SIU investigations.” This includes cases that were “handled through the Office of the Premier”.
Hospital CEOs
Also on Bloom’s radar are the appointments of Dr Nthabiseng Makgana, Dr Lehlohonolo Majake, and Dr Godfrey Mbara to positions of CEOs of Chris Hani Baragwanath, Steve Biko and George Mukhari academic hospitals respectively.
The appointments were made in March, and health MEC Nomantu Nkomo-Ralehoko responded to Bloom’s questions about them in October. Bloom highlighted irregularities, noting that none of the three appointees met the requirement of 8 to 10 years of experience for hospital CEO roles, while one also didn’t have the required education qualification level. These are contraventions of regulations, according to Bloom, adding that he is still to see proof of qualifications, as he’s requested.
Another high-profile appointment under scrutiny has been the redeployment of Dr Nozuko Makabayi – the former CEO of the Rahima Moosa Mother and Child Hospital. A doctor’s open letter in June 2022 exposed poor conditions at the hospital, leading to a Health Ombud investigation. The damning report criticised Makabayi for several failings, including being absent from work for nearly 100 days without explanation. The Ombud recommended that Mkabayi be removed as CEO, but she was shifted within the department to serve as acting director responsible for HIV and Aids, STIs and TB.
Bloom’s follow-up questions to Nkomo-Ralehoko brought to light that Makabayi has not been reporting for work, due to mental health stress, but continues to receive her salary. “This is outrageous. After all the trouble she caused, she is now on a long running paid holiday at taxpayers’ expense. If she can’t do any useful job, she should be medically boarded and leave the department,” he said in October.
“There has not been a permanent HR director for years in the department and the systems of appointments follow a consistent pattern of people placed in acting positions, protecting interests, and ensuring cadre deployment rather than service delivery,” Bloom told Spotlight.
“We have the wrong people in these key positions by design. We are talking about control, looting and siphoning of one of the largest budgets in the province,” he alleged.
Modiba said that “relevant bodies are investigating” and pertaining specifically to Makabayi, he said “internal processes are unfolding” but cannot be released to the media because of an “employer-employee clause”.
Scathing Auditor General report
Recently, the Gauteng Department of Health received another scathing report from the Auditor-General for the 2023/24 financial year.
The department underspent by R1.1 billion, including R590 million underspent on the National Tertiary Service Grant intended for specialised medical treatment. This in spite of backlogs and long patient waiting lists. In addition, the report showed that the health department racked up R2.7 billion in irregular spending, R17 million in wasteful spending, and lost another R2.7 billion in income.
Action SA member in the provincial legislature Emma More described the performance of the department as “clearly lacking effective leadership and management”.
She slammed the health department for providing incorrect and misleading statistics, as highlighted by the auditor-general. “For an institution like the [Gauteng] Health Department to provide such misleading information undermines public confidence in it and compromises the lives of our citizens in this province,” More said. “It is unacceptable that while our healthcare facilities are under-resourced and struggling to meet the needs of the population, significant portions of the budget are being wasted or mismanaged.”
Responding to More’s comments, Modiba said that the department had spent 98.9% of its budget allocated for 2023/2024. He said that of the 1.1% (R1.1 billion) under expenditure, R580 million has already been provisionally approved by Treasury to be carried over to the current fiscal year, subject to audited financial statements.
“While the department aims to spend every allocated cent, achieving this goal is not always feasible due to various factors impacting the operational environment. For instance, some of the money was committed to purchase orders or invoices that could not be processed within the previous financial year leading to a rollover of funds. The amount covers grants for human resource training, national tertiary services, district health programmes and the national health insurance,” Modiba said.
A ‘structural’ problem
Professor Alex van den Heever, chair of social security systems administration and management Studies at Wits University’s School of Governance, said the health department’s leadership crisis at its core is a structural one.
“South Africa has a huge pool of talent, and we are not short on good managers or people who understand health, and how to run a health service – but these are exactly the people the [Gauteng] department of health don’t want,” he said.
“Why would they want a Babita Deokaran [an acting chief financial officer who was assassinated in August 2021 after flagging what appeared to be corruption at Tembisa Hospital] or someone who is actually going to root out the nonsense or someone who is going to properly manage patient care?” Van den Heever asked.
Describing the department’s leadership as an “hourglass model”, Van den Heever said at the top are leaders with all the power, but little focus is on delivery. The pressure falls on an overstressed, underfunded middle management with limited decision-making power, which then trickles down as problems for those at the bottom.
He added: “Hospitals can’t afford this kind of leadership, they fall apart. There is no strategy behind anything, so no maintenance, proper training and supervision of staff or clinical governance. Problems aren’t solved, they’re hidden.”
Spotlight questioned the department’s alleged failure to attract “fit for purpose” candidates, resulting in more leadership and governance challenges for the department that filter down to hospital and clinic level.
In response, Modiba stated that, for the first time since 2006, they have reviewed organisational structures, which have now been submitted to the Office of the Premier.
“This is a major step towards ensuring that the Gauteng Department of Health has a structure fit for purpose that is geared to meet the service needs of the growing Gauteng population. Furthermore, a service provider has been appointed for the next three years to conduct ‘personnel suitability checks’. This will assist the department in its recruitment of suitably qualified employees who will be able to contribute meaningfully towards the achievement of the organisation’s strategic objectives,” he added.
Offering a solution to fix some of the challenges crippling the health department, Van den Heever said that changing leadership structures to orient towards service delivery could mean better governance and management, improved staff motivation, renewed public confidence and ultimately better patient care. This, he said, would require the decentralisation of powers so that competent people can take charge in hospitals, make impactful decisions about appointments and budgets, and be accountable for pockets within a complex provincial health system.
Soccer heading may cause more damage to the brain than previously thought, according to a study presented at the annual meeting of the Radiological Society of North America (RSNA).
Heading is a widely used technique in soccer where the players control the direction of the ball by hitting it with their head. In recent years, research has been done that suggests a link between repeated head impacts and neurodegenerative diseases, such as chronic traumatic encephalopathy (CTE).
“The potential effects of repeated head impacts in sport are much more extensive than previously known and affect locations similar to where we’ve seen CTE pathology,” said study senior author Michael L. Lipton, MD, PhD, professor of radiology at Columbia University Irving Medical Center. “This raises concern for delayed adverse effects of head impacts.”
While prior studies have identified injuries to the brain’s white matter in soccer players, Dr Lipton and colleagues used a new approach in diffusion MRI to analyse microstructure close to the surface of the brain.
To identify how repeated head impacts affect the brain, the researchers compared brain MRIs of 352 male and female amateur soccer players, ranging in age from 18 to 53, to brain MRIs of 77 non-collision sport athletes, such as runners.
Soccer players who headed the ball at high levels showed abnormality of the brain’s white matter adjacent to sulci, which are deep grooves in the brain’s surface. Abnormalities in this region of the brain are known to occur in very severe traumatic brain injuries.
The abnormalities were most prominent in the frontal lobe of the brain, an area most susceptible to damage from trauma and frequently impacted during soccer heading. More repetitive head impacts were also associated with poorer verbal learning.
“Our analysis showed that the white matter abnormalities represent a mechanism by which heading leads to worse cognitive performance,” Dr Lipton said.
Most of the participants of the study had never sustained a concussion or been diagnosed with a traumatic brain injury. This suggests that repeated head impacts that don’t result in serious injury may still adversely affect the brain.
“The study identifies structural brain abnormalities from repeated head impacts among healthy athletes,” Dr Lipton said. “The abnormalities occur in the locations most characteristic of CTE, are associated with worse ability to learn a cognitive task and could affect function in the future.”
The results of this study are also relevant to head injuries from other contact sports. The researchers stress the importance of knowing the risks of repeated head impacts and their potential to harm brain health over time.
“Characterising the potential risks of repetitive head impacts can facilitate safer sport engagement to maximise benefits while minimising potential harms,” Dr Lipton said. “The next phase of the study is ongoing and examines the brain mechanisms underlying the MRI effects and potential protective factors.”
Killer T cells about to destroy a cancer cell. Credit: NIH
Researchers have discovered a genomic ‘brake’ in a subset of immune cells that could help advance immunotherapy for cancer and autoimmune disease. The findings, led by a team at the Peter MacCallum Cancer Centre in collaboration with researchers at the Garvan Institute and Kirby Institute, provide new insights into how the body’s immune defence mechanisms can go awry in these diseases and open a new class of potential drug targets that could activate immune cells in tumour tissue.
The research was published in the journal Immunity.
Discovering an immune brake
Specialised killer T cells are released during an infection, trained to recognise and destroy the threat. When unchecked, these cells can cause autoimmune diseases such as type 1 diabetes or rheumatoid arthritis if they mistakenly attack the body’s own healthy tissues.
The immune system employs a mechanism to prevent autoimmune attacks called ‘tolerance’ – a process that can be exploited by cancer cells to shield them from the body’s natural defences.
“Until now, it was not fully understood how tolerance works at a molecular level. We used advanced sequencing techniques to identify a unique genomic signature in ‘tolerant’ T cells that differentiated them from killer T cells that were activated in response to viral infection,” says Dr Timothy Peters, co-first author from Garvan.
“These precise genome locations have never before been observed and allowed us to track precisely how killer T cells progress through the tolerance pathway, and how specific gene networks enable tolerance to be abused.”
Breakthrough for cancer and autoimmune disease
Dr Ian Parish, who led the research at the Peter MacCallum Cancer Centre said this breakthrough helps to understand why cancer treatments fail and opens the door to developing new treatments in the future.
“Current cancer immunotherapy treatments target the exhaustion phase of the immune response,” he said. “Our research suggests that a second, earlier ‘off-switch’ called tolerance may explain how many cancers resist current immunotherapies by blocking anti-cancer immunity from getting off the ground. We’re excited as these findings can be exploited for new treatments. Our next step is to understand if we can disrupt tolerance and engage the immune system to restart and attack those cancers resistant to treatment.”
Professor Chris Goodnow, Head of the Immunogenomics Lab at Garvan, says this new understanding of T cell tolerance opens up opportunities to develop new drugs that could selectively alter this pathway.
“The discovery of these gene locations provides us with a roadmap for developing future drugs, which could block the tolerance mechanisms to boost cancer-killing ability for immunotherapies. Conversely, for autoimmune diseases, enhancing tolerance could prevent harmful autoimmune attack,” he says.
In next steps, the researchers will focus on understanding how to disrupt the tolerance mechanism and engage the immune system to restart.
“These findings have revealed around 100 new potential targets for drugs to target the tolerance mechanism in T cells, which have until now been largely developed by trial and error,” says Professor Goodnow. “This could lead to a whole new class of treatments for autoimmunity and cancer.”
Professor Chris Goodnow is The Bill and Patricia Ritchie Foundation Chair and Director of the Cellular Genomics Futures Institute, UNSW Sydney. Dr Tim Peters is a Conjoint Lecturer at St Vincent’s Clinical School, UNSW Medicine and Health.
Researchers have analysed the effects of seven different hormone treatments for menopausal symptoms, and the risk of blood clots, stroke and heart attack. The risks differ depending on the active substance and how the medicine is taken, according to the study findings which appear in the BMJ. In this world’s largest and most comprehensive study of currently prescribed hormonal substances, researchers analysed the risks for one million women aged 50–58.
“There is concern among women that menopausal hormone therapy increases the risk of cardiovascular disease. This concern is based on older studies conducted more than 20 years ago that only looked at one type of treatment. Since then, many new preparations have been introduced and our study shows that the previous conclusions do not apply to all types of treatments,” says Therese Johansson, postdoctoral researcher and lead author of the study, which was part of her thesis at Uppsala University.
To counteract the health effects of menopause, such as hot flashes and osteoporosis, women may be prescribed hormone replacement therapy which consists of hormones or hormone-like substances.
Treatment available since the 1970s
In Sweden alone, hundreds of thousands of women currently use hormone replacement therapy and this type of treatment has been available since the 1970s. At that time, there was only one type of hormone replacement therapy and when a major study in the 1990s showed that it increased the risk of cardiovascular disease, its use rapidly declined. Since then, new preparations have entered the market, and following this, the use of hormone replacement therapy in connection with menopause has increased significantly in recent years.
In the new study, the researchers looked at seven different types of currently used hormone replacement treatments, administered via tablets, hormone patches or hormone-releasing IUDs. The study is based on all prescriptions for hormone replacement therapy in Sweden from 2007 to 2020 and covers nearly one million women aged 50 to 58. The women were monitored for two years after starting hormone replacement therapy. The risk of blood clots and cardiovascular disease was compared between women who had and had not collected a prescription medicine for hormone replacement therapy.
Different therapies, different risks
The results show clearly that the risks of hormone replacement therapy vary depending on the type of treatment.
For example, the synthetic hormone tibolone, which mimics the effects of the body’s natural hormones, was linked to an increased risk of both heart attack and stroke, but not to an increased risk of blood clots. The risk of heart attack or stroke due to tibolone is estimated at one in a thousand women.
Combined preparations containing both oestrogen and progesterone instead increase the risk of blood clots, including deep vein thrombosis and pulmonary embolism. The researchers estimate that the risk of deep vein thrombosis resulting from this combined preparation is about 7000 women per year.
“It is important that both doctors and women are aware of the risks of menopausal hormone therapy and, in particular, that the existing drugs carry different risks of blood clots and cardiovascular disease. Tibolone in particular was associated with an increased risk of stroke and heart attack. Tibolone is used in Europe but is not approved in countries such as the United States. We hope that our study will lead to the drug being withdrawn from use here as well,” says Åsa Johansson, research group leader at Uppsala University and SciLifeLab, and the study’s senior author.
During the period of the study, 2007–2020, a roughly 50% increase hormone patch use was observed, and these preparations were not linked to the same higher risk. The increased use of safer alternatives, such as patches, is an important step forward in reducing the risk of cardiovascular disease among menopausal women.
Identify individual increased risk
“The next step in our research will be to develop strategies to identify which women are at increased risk of certain diseases in connection with using hormonal drugs. In this way, we can guide patients to the most appropriate medicine for each individual and drastically reduce the number of side effects,” Åsa Johansson says.
A fascinating new study, published in the Journal of Clinical Investigation, has revealed an unexpected potential benefit of severe COVID infection: it may help shrink cancer.
This surprising finding, based on research conducted in mice, opens up new possibilities for cancer treatment and sheds light on the complex interactions between the immune system and cancer cells – but it certainly doesn’t mean people should actively try to catch COVID.
The data outlining the importance of the immune system in cancer is considerable and many drugs target the immune system, unlocking its potential, an important focus of my own research.
The study here focused on a type of white blood cell called monocytes. These immune cells play a crucial role in the body’s defence against infections and other threats. However, in cancer patients, monocytes can sometimes be hijacked by tumour cells and transformed into cancer-friendly cells that protect the tumour from the immune system.
What the researchers discovered was that severe COVID infection causes the body to produce a special type of monocyte with unique anti-cancer properties. These “induced” monocytes are specifically trained to target the virus, but they also retain the ability to fight cancer cells.
To understand how this works, we need to look at the genetic material of the virus that causes COVID. The researchers found that these induced monocytes have a special receptor that binds well to a specific sequence of COVID RNA. Ankit Bharat, one of the scientists involved in this work from Northwestern University in Chicago explained this relationship using a lock-and-key analogy: “If the monocyte was a lock, and the COVID RNA was a key, then COVID RNA is the perfect fit.”
Remarkable
To test their theory, the research team conducted experiments on mice with various types of advanced (stage 4) cancers, including melanoma, lung, breast and colon cancer. They gave the mice a drug that mimicked the immune response to a severe COVID infection, inducing the production of these special monocytes. The results were remarkable. The tumours in the mice began to shrink across all four types of cancer studied.
Unlike regular monocytes, which can be converted by tumours into protective cells, these induced monocytes retained their cancer-fighting properties. They were able to migrate to the tumour sites – a feat that most immune cells cannot accomplish – and, once there, they activated natural killer cells. These killer cells then attacked the cancer cells, causing the tumours to shrink.
This mechanism is particularly exciting because it offers a new approach to fighting cancer that doesn’t rely on T cells, which are the focus of many current immunotherapy treatments.
While immunotherapy has shown promise, it only works in about 20% to 40% of cases, often failing when the body can’t produce enough functioning T cells. Indeed it’s thought that the reliance on T cell immunity is a major limitation of current immunotherapy approaches.
This new mechanism, by contrast, offers a way to selectively kill tumours that is independent of T cells, potentially providing a solution for patients who don’t respond to traditional immunotherapy.
It’s important to note that this study was conducted in mice, and clinical trials will be necessary to determine if the same effect occurs in humans.
Maybe aspects of this mechanism could work in humans and against other types of cancer as well, as it disrupts a common pathway that most cancers use to spread throughout the body.
While COVID vaccines are unlikely to trigger this mechanism (as they don’t use the full RNA sequence as the virus), this research opens up possibilities for developing new drugs and vaccines that could stimulate the production of these cancer-fighting monocytes.
Few would have imagined that there’d be an upside to COVID. Photo by Kelly Sikkema on Unsplash
Trained immunity
The implications of this study extend beyond COVID and cancer. It shows how our immune system can be trained by one type of threat to become more effective against another. This concept, known as “trained immunity”, is an exciting area of research that could lead to new approaches for treating a wide range of diseases.
However, it’s crucial again to emphasise that this doesn’t mean people should seek out COVID infection as a way to fight cancer, and this is especially dangerous as I have described. Severe COVID can be life-threatening and has many serious long-term health consequences.
Instead, this research provides valuable insights that could lead to the development of safer, more targeted treatments in the future. As we continue to grapple with the aftermath of the COVID pandemic, new infections and long COVID, studies like this remind us of the importance of basic scientific research.
Even in the face of a global health crisis, researchers are finding ways to advance our understanding of human biology and disease. This work not only helps us combat the immediate threat of COVID, but also paves the way for breakthroughs in treating other serious conditions such as cancer.
While there’s still much work to be done before these findings can be translated into treatments for human patients, this study represents an exciting step forward in our understanding of the complex relationship between viruses, the immune system and cancer. It offers hope for new therapeutic approaches and underscores the often unexpected ways in which scientific discoveries can lead to medical breakthroughs.
Biological entities called obelisks have been hiding – in large numbers – inside the human mouth and gut. These microscopic entities, which were recently discovered by a team at Stanford University, are circular bits of genetic material that contain one or two genes and self-organise into a rod-like shape.
Although the study is still in preprint form, meaning that it has not been peer-reviewed, it has already been extensively written about, including in two heavyweight journals: Nature and Science.
Let’s delve deeper into the strange world of very tiny “lifeforms”.
In biology, as in physics, things can get weirder and the rules fuzzier as we move through smaller and smaller scales.
Viruses, being unable to replicate without the help of a host, can most generously be considered to be on the edge of what constitutes life. Yet the estimated 10 nonillion (one followed by 31 zeroes) individual viruses on the planet can be found in every conceivable habitat and, through infecting and manipulating their hosts, have probably affected the evolutionary trajectories of all life.
Peering even further down into the world of minuscule biological entities, are the viroids – tiny scraps of genetic material (DNA-like molecules known as RNA) that cannot make proteins and, unlike viruses, don’t have a protective shell to encase their genome.
Viroids are examples of ribozymes: RNA molecules that may be a distant echo of the very first self-replicating genetic elements from which cellular life emerged.
Viroids can self-cleave (chop up) and re-ligate (stick back together) their genome as part of the replication cycle. And, despite their simplicity, they can cause serious disease in flowering plants.
Between a virus and a viroid – perhaps
The new preprint describes “viroid-like colonists of human microbiomes”. If “viroid-like” sounds non-committal, that is entirely deliberate. The newly discovered biological entity falls somewhere between viruses and viroids.
In fact, the name obelisks was proposed not only because of their shape, but also to provide wiggle room in case they turn out to be more like RNA plasmids (a different type of genetic element that resides inside bacteria) than either viruses or viroids.
Like viroids, obelisks have a circular single-stranded RNA genome and no protein coat but, like viruses, their genomes contain genes that are predicted to code for proteins.
All obelisks so far described encode a single major protein known as obulin, and many encode a second, smaller obulin.
Obulins bear no evolutionary resemblance, or “homology”, to any other protein found, and there are few clues as to their function.
By analysing existing datasets taken from the gut and mouth of humans as well as other diverse sources, the Stanford team found almost 30,000 distinct obelisk types.
These obelisk genomes have been previously overlooked because they are so dissimilar to anything described previously. The Stanford team found them using a clever bespoke method for searching databases for single-stranded circular RNA molecules to fish out any viroid-like elements.
It is clear from their results that obelisks are not rare. The researchers found them in datasets spanning the globe and in diverse niches.
These elements were detected in around 7% of microbiome datasets from the human gut and 50% of datasets from the mouth. However, whether these datasets provide a true representation of the prevalence and distribution of obelisks is unclear.
Different obelisk types were found in different body sites and in different donors. Long-term data revealed that people can harbour a single obelisk type for around a year.
Obelisks probably rely on microbial host cells to replicate, including those that live inside humans to replicate. Bacteria or fungi are likely hosts, but it is not known which exact species harbour these elements.
However, the researchers provide a critical lead through the analysis by providing strong evidence that a common bacterial component of dental plaque, Streptococcus sanguinis, plays host to a specific obelisk type.
We might have to rethink the gut microbiome. Credit Darryl Leja National Human Genome Research Institute National Institutes Of Health
Friend or foe?
As S sanguinis is easy to grow and experiment on in the laboratory, this will provide a valuable model for understanding the fundamentals of obelisk biology.
This is critical, as nothing is known about the broader evolutionary and ecological significance of obelisks. They may be parasitic and harm host cells, or they may be beneficial.
Hosts may have evolved elaborate defence mechanisms against obelisks, or else actively recruit them to gain some unsuspected advantage. If obelisks change or upset the human microbiome, this may in turn have implications for human health – they may even have therapeutic potential.
Alternatively, obelisks may cause neither harm nor benefit to their microbial host, or to humans. Instead, they may simply exist as stealthy evolutionary passengers, silently and endlessly replicating, like the original “selfish gene”.
Photo by Miguel Á. Padriñán: https://www.pexels.com/photo/syringe-and-pills-on-blue-background-3936368/
For oral medications that prevent new HIV infection to be effective, the patient must take certain actions, including attending doctor’s visits every three months and – most importantly – consistency.
These daily oral antiretrovirals, more commonly referred to as PrEP (pre-exposure prophylaxis), such as Truvada®, are extremely effective at HIV prevention, but only if they are taken daily as directed. Truvada’s efficacy is greatly compromised when taken inconsistently.
However, results from a recent Gilead-funded clinical trial (Purpose-2) led by physicians at Emory University and Grady Health System indicate that a twice-yearly injection of Lenacapavir offers a 96% reduced risk of infection overall, making the injection significantly more effective than the daily oral PrEP. The findings were recently published in the New England Journal of Medicine.
“Seeing these high levels of efficacy – at almost 100% – in an injectable that people only have to take every six months is incredible,” says Colleen Kelley, MD, lead author of the study and professor in the School of Medicine at Emory University. “This is a considerable and profound advancement in medicine, especially for people whose circumstances don’t allow them to take a daily oral medication, and for those among populations disproportionately impacted by HIV.”
In the randomised, double-blind, Phase III clinical trial comparing the efficacy of the two medications, 99% of the participants in the Lenacapavir group did not acquire an HIV infection. During the trial, only two participants in the Lenacapavir group, comprised of 2,179 people, acquired HIV. This compares to nine new HIV infections in the Truvada®group, which had 1,086 people. The trial showed that adherence to the injectable was higher than of the daily oral pill.
Kelley adds that while PrEP is incredibly effective at preventing infection, part of what made the injection more effective in the clinical trial was the challenges associated with adherence to a daily oral pill.
“What we see over time is that about half of people who start taking daily oral PrEP stop within a year due to various factors,” says Kelley, referencing healthcare disparities in general. “Having an effective injectable that is only needed twice annually is very significant for people who have trouble accessing healthcare or staying adherent to daily, oral pills.”
The inclusion of racially, ethnically, and gender-diverse participants in the clinical trial was notable because it was representative of populations disproportionately impacted by HIV in real time. For example, the trial groups were comprised of cisgender men and gender-diverse people at 88 sites in Peru, Brazil, Argentina, Mexico, South Africa, Thailand, and the US.
According to the study, the same populations that are disproportionately impacted by HIV are the same populations that have limited access to PrEP – or may have difficulty consistently taking the oral antiretroviral medication – ultimately highlighting the need for more options. The study also indicates that more than half of the new HIV infections nationwide in 2022 were among cisgender gay men, and 70% of those were among Black or Hispanic individuals.
Valeria Cantos, MD, associate professor in the School of Medicine at Emory University, physician at Grady Memorial Hospital, and the principal investigator for the clinical trial at the Grady research site, emphasized the importance of having trials that include populations truly representative of the patients that Grady serves.
“At Grady, our focus is on increased representation of underserved and vulnerable populations, acknowledging and addressing the distrust towards research held by some community members due to prior abuses or neglect of these populations by research institutions in the past,” Cantos says. “Grady is an established, trusted research site because of its commitment to equity.”
At the Grady clinical trial site, medical materials were available in Spanish, and bilingual staff members recruited and enrolled trial participants who only spoke Spanish. Cantos also indicated that the site enrolled participants who are representative of the populations that would benefit the most from Lenacapavir. In addition to Grady, the Hope Clinic and Emory Midtown Hospital were among the 88 sites supporting the clinical trial.
“We are not reaching everyone we need to reach with our current HIV prevention interventions, such as those who are disproportionately impacted by HIV and health care disparities,” says Kelley. “For people that are unable to take the daily oral pills, the injectable agents can really give incredible efficacy and be a game changer in helping them stay HIV negative.”
Since the Phase III clinical trial has been completed and submitted by the FDA for consideration, Kelley is hopeful that Lenacapavir may be approved by 2025 for commercial use.
An injection given during some asthma and COPD attacks was shown to be more effective than the current treatment of steroid tablets, reducing the need for further treatment by 30%. The findings, published in The Lancet Respiratory Medicine, could be “game-changing” for millions of people with asthma and COPD around the world, scientists say.
The type of symptom flare-up the injection treats are called ‘eosinophilic exacerbations’ and involve symptoms such as wheezing, coughing and chest tightness due to inflammation resulting from high amounts of eosinophils, a type of white blood cell. Eosinophilic exacerbations make up to 30% of COPD flare-ups and almost 50% of asthma attacks. They can become more frequent as the disease progresses, leading to irreversible lung damage in some cases.
Treatment at the point of an exacerbation for this type of asthma has barely changed for over fifty years, with steroid drugs being the mainstay of medication. Steroids such as prednisolone can reduce inflammation in the lungs but have severe side-effects such as diabetes and osteoporosis. Furthermore, many patients ‘fail’ treatment and need repeated courses of steroids, re-hospitalisation or die within 90 days.
Results from the phase two clinical trial ABRA study, led by scientists from King’s College London and sponsored by the University of Oxford, show a drug already available can be re-purposed in emergency settings to reduce the need for further treatment and hospitalisations. The multi-centre trial was conducted at Oxford University Hospitals NHS Foundation Trust and Guy’s and St Thomas’ NHS Foundation Trust.
Benralizamab is a monoclonal antibody which targets eosinophils to reduce lung inflammation. It is currently used for the treatment of severe asthma. The ABRA trial has found a single dose can be more effective when injected at the point of exacerbation compared to steroid tablets.
The study investigators randomised people at high risk of an asthma or COPD attack into three groups, one receiving benralizumab injection and dummy tablets, one receiving standard of care (prednisolone 30mg daily for five days) and dummy injection and the third group receiving both benralizumab injection and standard of care. As a double-blind, double-dummy, active-comparator placebo-controlled trial, neither the people in the study, or the study investigators knew which study arm or treatment they were given.
After 28 days, respiratory symptoms of cough, wheeze, breathlessness and sputum were found to be better with benralizumab. After 90 days, there were four times fewer people in the benralizumab group that failed treatment compared to standard of care with prednisolone.
Treatment with the benralizumab injection took longer to fail, meaning fewer episodes to see a doctor or go to hospital. Quality of life also improved for people with asthma and COPD.
This could be a game-changer for people with asthma and COPD. Treatment for asthma and COPD exacerbations have not changed in fifty years despite causing 3.8 million deaths worldwide a year combined.
– Lead investigator of the trial Professor Mona Bafadhel from King’s Centre for Lung Health
She added: “Benralizumab is a safe and effective drug already used to manage severe asthma. We’ve used the drug in a different way – at the point of an exacerbation – to show that it’s more effective than steroid tablets which is the only treatment currently available. The big advance in the ABRA study is the finding that targeted therapy works in asthma and COPD attacks. Instead of giving everyone the same treatment, we found targeting the highest risk patients with very targeted treatment, with the right level of inflammation was much better than guessing what treatment they needed.”
The benralizumab injection was administered by healthcare professionals in the study but can be potentially administered in the GP practice or in the Emergency Department. Benralizumab was safe in the study and similar in safety to many past studies.
Professor Mona Bafadhel said, “We hope these pivotal studies will change how asthma and COPD exacerbations are treated for the future, ultimately improving the health for over a billion people living with asthma and COPD across the world.”
The biggest and most comprehensive analysis of glucagon-like peptide-1 (GLP-1) receptor agonists on kidney and cardiovascular outcomes shows they have significant benefits in people with and without diabetes.1 Findings appear in The Lancet Diabetes & Endocrinology.
Originally developed to treat diabetes, GLP-1 receptor agonists mimic the action of glucagon-like peptide 1, a hormone which stimulates insulin production and lowers blood sugar levels. More recently, they have emerged as effective treatments for obesity – slowing digestion, increasing satiety and reducing hunger.
But while the benefits of GLP-1 receptor agonists for the treatment of type 2 diabetes, obesity and cardiovascular disease are well known, their impact on chronic kidney disease (CKD) has been less certain.
Researchers conducted a meta-analysis of 11 large-scale clinical trials of GLP-1 receptor agonists involving a total of 85 373 people (79.4% with type 2 diabetes and 20.6% with overweight or obesity and cardiovascular disease but without diabetes). Seven different GLP-1 receptor agonists were investigated among the trials.
The results showed that compared to placebo, GLP-1 receptor agonists reduced the risk of kidney failure by 16% and the worsening of kidney function by 22% (defined by a drop in estimated glomerular filtration rate – a measure of how much blood the kidneys filter clean every minute – of at least 50%). The combined reduction in the risk of kidney failure, worsening kidney function, and death due to kidney disease was 19%.
The analysis also confirmed previous findings that GLP-1 receptor agonists protect cardiovascular health, with a 14% reduction in the risk of cardiovascular death, non-fatal heart attack, and non-fatal stroke, compared to placebo. Death by any cause was 13% lower among patients treated with GLP-1 receptor agonists.
Lead author Professor Sunil Badve, Professorial Fellow at The George Institute for Global Health and UNSW Sydney said the study expanded current knowledge about this class of drugs in key areas, including benefits in people with CKD, and in people with and without diabetes.
“This is the first study to show a clear benefit of GLP-1 receptor agonists on kidney failure or end-stage kidney disease, suggesting they have a key role in kidney-protective and heart-protective treatment for patients with common medical conditions like type 2 diabetes, overweight or obesity with cardiovascular disease, or CKD,” he said.
“These results are particularly important for patients with chronic kidney disease. It is a progressive condition eventually leading to kidney failure requiring dialysis or kidney transplantation and is associated with premature death, mostly from heart disease. It has a significant impact on patients’ quality of life and incurs substantial healthcare costs.”
CKD is estimated to affect one in ten people worldwide, equivalent to around 850 million people.2 It is the tenth leading cause of death and is projected to become the fifth most common cause of death by 2050.3 Diabetes, cardiovascular disease and obesity are independent risk factors for CKD and represent a major global health burden.4
Badve S et al. Effects of glucagon-like peptide-1 receptor agonists on kidney and cardiovascular disease outcomes: a meta-analysis of randomised controlled trials. Lancet Diabetes Endocrinol. 2024. https://doi.org/10.1016/S2213-8587(24)00271-7
Jager KJ, et al. A single number for advocacy and communication-worldwide more than 850 million individuals have kidney diseases. Kidney Int. 2019. https://doi.org/10.1016/j.kint.2019.07.012
GBD 2021 Forecasting Collaborators. Burden of disease scenarios for 204 countries and territories, 2022–2050: a forecasting analysis for the Global Burden of Disease Study 2021. Lancet. 2024. https://doi.org/10.1016/S0140-6736(24)00685-8
The Global Burden of Metabolic Risk Factors for Chronic Diseases Collaboration. Cardiovascular disease, chronic kidney disease, and diabetes mortality burden of cardio-metabolic risk factors between 1980 and 2010: comparative risk assessment. Lancet Diabetes Endocrinol. 2015. https://doi.org/10.1016/S2213-8587(14)70102-0
