As spring arrives in South Africa, many people experience their most challenging allergy season. However, while pollen-filled air triggers obvious seasonal symptoms, allergies extend far beyond springtime discomfort, affecting millions year-round through food sensitivities, skin reactions, and environmental triggers.
“Spring allergies are usually just the tip of the iceberg,” says Tyron Hansen, Business Development Manager at BioSmart Lab. “You wake to spring sunshine and nature in full bloom, but instead of enjoying it, you’re shut inside with tissues and antihistamines. Meanwhile, your stomach acts up after breakfast, and that mysterious rash on your arms is back. Sound familiar?”
Hansen explains that many people assume that their symptoms stem from a single source, like pollen or food preservatives. However, BioSmart Lab’s test results often reveal they’ve actually been living with multiple triggers they never connected to their symptoms.
Why It’s Worth Looking Deeper
Professional allergen tests measure specific antibodies in your blood to identify how your body reacts to different substances. This matters because what looks like “seasonal” hay fever might actually be a mix of environmental, food, and even skin-related triggers.
“Our immune systems are like complicated alarm systems,” explains Hansen. “They go off loudly, but without proper testing, you only hear the siren – you don’t see what’s actually setting it off.”
A major source of confusion is the difference between allergies and intolerances. Both of which can make you feel unwell, but function very differently:
Allergies: They set off the immune system through immunoglobulin E (IgE) antibodies, causing anything from a runny nose or itchy eyes to potentially life-threatening anaphylaxis, often within minutes of exposure.
Intolerances: These don’t set off your immune system, but they can still cause digestive discomfort like bloating or nausea, and while not dangerous, they can nevertheless affect daily life.
“Knowing which is which can be the key to finally feeling better,” he adds.
Everyday Triggers You Might Be Missing
Allergies aren’t always obvious or seasonal. Many people live with daily discomfort without realising what’s behind it. Hansen provides some of the most common sources of ongoing allergic reactions.
Environmental triggers: Dust mites, mould spores, pet dander, and certain plants can cause year-round congestion, itchy eyes, or skin flare-ups.
Food sensitivities: That heavy, bloated feeling after meals could point to, for example, wheat, rice and corn sensitivity, or even certain food combinations.
Skin reactions: Chronic eczema or rashes are sometimes triggered by hidden allergens, not simply “sensitive skin.”
Allergic clues in children: Kids often can’t articulate their symptoms. What might appear to be frequent colds, skin rashes, or trouble concentrating could be subtle signs of allergies.
“Trying to figure out if your symptoms are caused by allergens through elimination diets, behavioural adjustments, or symptom tracking can take months and still leave you without answers, notes Hansen. “Blood-based testing provides a faster alternative by measuring IgE antibodies – the proteins your immune system releases when it detects threats.”
Taking Back Control
BioSmart Lab’s advanced blood panels analyse these IgE proteins across multiple allergens simultaneously. These tests can be purchased online and provide accurate, quantitative results without the risk of sparking reactions or being influenced by medication use.
Some people discover that they need to remove wheat to manage food allergies. Others learn that their “pet allergy” is actually a dust mite sensitivity. Parents often find their child’s mid-afternoon meltdowns are directly linked to specific food triggers at lunch.
“The goal isn’t just to manage symptoms – it’s to restore people’s quality of life,” emphasises Hansen. “Once you understand what your body is reacting to, you can move from frustrating guesswork to making informed choices, giving you control of your health back,” he concludes.
A dire picture for HIV/Aids funding emerged at the 12th South African AIDS Conference, raising the call for resilience, adapting and also for government to raise its game.
The what-next of South Africa’s HIV response will have to be centred on getting back to basics, leveraging on advances in treatment options and learning fast about adapting in a world without US aid for health services.
These were among the key takeaways from speakers at a plenary session at the 12th Southern African Aids Conference held in Kempton Park last week.
Professor Linda-Gail Bekker, executive officer of the Desmond Tutu Health Foundation, in her address took stock of “the incredible devastation around the world” from the virtual overnight shutting off of funds and human resources as Donald Trump returned to the US presidency in January 2025.
“It was $460 million into the wood chipper for us. And the worrying thing is that it could take us back to the harrowing scenes of 2000 [the height of Aids deaths in the country],” she said.
This comes against what she called the two largest challenges for South Africa’s HIV response: sub-optimal 12-month retention in care and viral suppression. Meaning the struggle to keep patients on treatment beyond a year and helping them stay on antiretrovirals that reduce the amount of virus in the body to a minimum.
The picture painted by Bekker and others is bleak, with much uncertainty remaining as to how South Africa might plug the funding holes left by the abrupt US aid cuts.
Bekker shared research by the Health Economics and Epidemiology Research Office (HE²RO), a division of the Wits Health Consortium at the University of the Witwatersrand. Their research shows that the fallout in the next three years could see South Africa experience a 29% to 56% increase in new HIV infections, or an additional 150 000 to 295 000 cases by 2028. Unless the South African government is able to take over services, there could be a 33% to 38% increase, or an additional 56 000 to 65 000 AIDS-related deaths in that period. (Spotlight previously reported on the HE²RO modelling in more detail here.)
The modelling also suggests that government will need additional funding of between $620 million and $1.4 billion (roughly R10 billion to R24 billion) between 2025 and 2028 to replace the local services that received US government funding.
In July, Treasury allocated R763 million in emergency funding to fill the gap, a fraction of what the HE²RO researchers estimate is needed. In addition, the Gates Foundation and the Wellcome Trust pledged R100 million each for research to the South African Medical Research Council on condition that the South African government doubled their contributions, which government committed to over three years. This added up to an R600 million bailout for research, also a fraction of the amount of research funding that has been lost.
Throughout the conference, there was also strong calls from attendees and speakers for government to be more transparent about its plans to mitigate the funding cuts and to provide credible data and information about monitoring and measuring of the success of their interventions. This includes details on how it plans to provide all stable patients with enough medicines for six months at a time. Such multi-month supplies mean people have to travel less to collect medicines, thus making it easier to stay on them. Rollout of multi-month dispensing has been very uneven across the country.
Questions were also raised over a lack of full transparency regarding the price of lenacapavir, a breakthrough HIV prevention injection that provides six months of protection per shot. As we recently reported, the South African government will be paying $60 per person per year for the jab, with other donors paying the rest – it is not publicly known how much this “rest” is. The deal was setup by the Global Fund to Fight AIDS, Tuberculosis and Malaria, Gilead Sciences – the company that makes lenacapavir – and several private donors. Last week, Spotlight published an op-ed in which activists questioned the lack of full transparency about the price.
Dr Sandile Buthelezi, director-general for the National Department of Health, told attendees about the possibility of bringing forward the rollout date for lenacapavir from April next year, to possibly as soon as November this year. He did not answer questions about the price negotiations. He did however confirm that negotiations with The Global Fund has seen them commit to ringfencing US$29 million for procurement of lenacapavir over the next two and a half years.
Doing more with less
Having to do more with less, Bekker said at the conference, will mean the need to build a “resilience bridge”. For her, this means preserving the “two most important interventions” of providing continued access to antiretroviral treatment and to HIV prevention treatments – both long-acting injections and prevention pills.
She added that it also means better efforts to reach the population of people living with HIV who have been diagnosed but are not on treatment. In February 2025, government launched its ‘Close the Gap’ campaign aimed at placing an additional 1.1 million people on treatment by the end of this year. Bekker said the number of people living with HIV who are not on treatment is closer to 2 million people. According to Thembisa, the leading mathematical model of HIV in the country, of the roughly eight million people living with HIV in South Africa, around 6.2 million are on treatment.
How South Africa is progressing against the 1.1 million target is not clear. Figures previously shared by Health Minister Dr Aaron Motsoaledi indicated that over half a million people had been initiated on treatment in a matter of months. This raised eyebrows since, on the face of it, it means that people had been started on treatment this year more quickly than at any other time in South Africa’s HIV response. It also wasn’t clear whether the number of people who had stopped treatment had been subtracted from the number starting treatment. Questions Spotlight previously sent to the health department seeking clarification of the numbers went unanswered. Similar questions were also raised in an open letter and an op-ed published by Spotlight and GroundUp. As yet, Spotlight has not seen answers to the questions raised about the numbers shared by the Minister.
“We need to make services [more] amenable to retention so it means multi-month dispensing and differentiated care,” Bekker said. Differentiated care refers to treating people differently based on their needs – for example by not requiring healthy people living with HIV to visit the clinic as often as sicker people.
“Bad policies that reflect ideology and bias, mean the most vulnerable are deterred from assessing the services they need, and this includes our key populations,” she added of the challenges that people like sex workers, members of the LGBTQI+ community and people who use drugs face in clinics where they are judged, harassed or discriminated against.
Dr Lise Jamieson, a senior researcher at HE²RO, echoed Bekker’s sentiments and said a first priority remains to arrest any backsliding of care as South Africa restructures its HIV programme to match the money it has currently. “It is clear that the one thing that we absolutely cannot drop is our HIV treatment programme – it saves lives,” she said.
For Yvette Raphael, the co-founder and co-director of Advocacy for the Prevention of HIV and Aids (APHA), the undergirding socio-economic factors that have given HIV its stranglehold in South Africa remain largely unchanged.
She said: “I am one of the people who are ageing with HIV and suffering from other non-communicable diseases that come with this”, highlighting the need to address the evolving nature of HIV in the country and the need to address it alongside conditions such as diabetes and heart disease.
But she added that it is still teen girls and young women who are at a disproportionately high risk of acquiring HIV. Her message was for better youth-targeted responses that are community-level responses not top-down strategies.
“Make HIV a priority sustained by local and district government structures, not up here in our national and province centres,” she said.
“Make HIV prevention harder to ignore and weave HIV intervention services with skills training and income generating programmes. We know that employment in this country is low, so young people cannot be expected to continue a healthy life without spaces where they can generate income for themselves, this will [in turn] reduce their vulnerability and dependency on older men.”
She added that government had to step up to what should always have been their role as Pepfar funding was never meant to substitute the work of government. Raphael said: “Pepfar was here to support the government in the early days of HIV. However, some of our government officials saw that as a way of evading their responsibility, and we are now here.”
Note: The Gates Foundation is mentioned in this article. Spotlight receives funding from the Gates Foundation, but is editorially independent – an independence that the editors guard jealously. Spotlight is a member of the South African Press Council and subject to the South African Press Code.
With females aged 25-34 showing a 255 percent surge in alcohol-related deaths during this time period
Credit: Pixabay CC0
In an analysis by race, sex, age, and geography, alcohol-induced death rates in 2024 are nearly double those in 1999, with a sharp increase at the onset of the COVID-19 pandemic. Although rates are higher for men, the largest increase in alcohol-induced deaths over the full 25-year period occurred in females aged 25-34, according to a study published on September 17 by Dr Tony Wong and colleagues at UCLA in the open-access journal PLOS Global Public Health.
Alcohol-induced deaths have been increasing over the past two decades. Particularly concerning are increases between 2019 and 2021, when the population was under significant stress from isolation due to the COVID-19 pandemic, and people with alcohol-use disorders were less able to access treatment. Quantifying mortality trends and determining whether alcohol-induced deaths have returned to pre-pandemic levels is essential for understanding long-term temporal patterns and dynamics. To examine these trends, the authors of this study analysed data from the Centers for Disease Control and Prevention’s National Vital Statistics System, focusing on 14 specific alcohol-induced causes of death.
Wong et al. found that rates of alcohol-induced deaths in the United States nearly doubled between 1999 and 2024, reaching their highest level in 2021. Most deaths are due to alcoholic liver disease and, to a lesser degree, alcohol-related mental and behavioural disorders. The largest overall increase in alcohol-induced mortality across all race, sex, age groups occurred in 2021 when fatalities peaked at 54,258 deaths overall. By 2024, fatalities had declined, but the average alcohol-induced mortality rate across U.S. counties remained approximately 25% higher than in 2019.
American Indian/Alaska Native populations (AIAN) remain the most affected, with male AIAN rates of alcohol-induced mortality three times higher than that of white males, and female AIAN mortality rates four times higher than that of white females, over the entire period of investigation.
The largest increase by demographic was among females aged 25-34, which rose from 0.9 deaths per 100 000 in 1999 to 3.2 per 100 000 in 2024 — a 255 percent increase. The second largest increase was in males aged 25-34, from 2.3 fatalities per 100 000 in 1999 to 6.5 in 2024 — a 188 percent increase. As deaths from chronic diseases related to alcohol use, such as certain cancers or cardiovascular events, were not included in this study, the overall fatality counts may be underestimated. These findings underscore the critical need for targeted policies to reduce excessive alcohol consumption and improve access to treatment for those who need it most.
Senior author Maria R D’Orsogna adds: “The rapid rise of alcohol-induced deaths among women is particularly concerning. Although men still die at higher rates, the gender gap appears to be closing. Notably, for the population aged 25-34, the male-to-female mortality ratio has decreased from three-to-one in 1999 to two-to-one in 2024.”
The authors conclude: “The rise in alcohol-induced mortality is widespread and affects the entire country, with particularly large surges arising during the COVID-19 pandemic. In the early months of the pandemic, alcohol-induced deaths among AIAN males increased by as much as 40% in a single month and remained unusually high for nearly four years. Similar trends were observed among AIAN and Black females, whose alcohol-induced death rates rose by over 30% in one month.”
Antiseizure medications help the majority of people with focal epilepsy, a common form of the neurological disorder. Yet most will still have episodes for at least a year after their treatment begins, until their doctors can find the right drug and dosage for them, a new study shows.
Accounting for about 60% of people with epilepsy, focal epilepsy occurs when nerve cells in a certain brain region send out a sudden, excessive burst of electrical signals. This uncontrolled activity, which is called a focal seizure, can cause problems such as abnormal emotions or feelings and unusual behaviours. Much attention has been paid to the minority of patients who do not respond well to available treatments, but the current study looks at another group: those who may not respond to the first medication or regimen prescribed but who might respond to another tried later.
Led by researchers at NYU Langone Health as part of the international Human Epilepsy Project, the study is among the first in a decade to focus on those whose seizures ultimately can be prevented or controlled with drugs. Results for nearly 450 men, women, and teens newly diagnosed with the disorder revealed that although more than half eventually received a medication or regimen that worked for them, major improvements were not achieved until an average of 12 months. Many needed even longer to find relief.
“Our findings suggest that those with focal epilepsy should expect a long adjustment period as their healthcare provider determines the best treatment regimen for them,” said study senior author and neurologist Jacqueline A. French, MD.
A possible explanation for this delay is that physicians are not selecting the ideal antiseizure therapy on their first try, adds Dr French, a professor in the Department of Neurology at the NYU Grossman School of Medicine and co-principal investigator of the Human Epilepsy Project.
Neurologists commonly start patients on levetiracetam, a drug that can target many types of seizures and has few interactions with other medications. Based on the new results, however, they may want to rethink this approach, says Dr French, noting that although 57% of the study participants were initially prescribed levetiracetam, only a quarter became seizure free on their first try.
Thirty-four epilepsy centres in the United States, Europe, and Australia were involved in the study, which took place from 2012 to 2019. The team collected data about the patients’ medical histories, demographic factors, and the details of their epilepsy diagnoses. All were provided annual follow-ups for either three or six years.
During this time, participants tracked their seizure frequency in an electronic diary, describing each day as either “seizure-free” or “had a seizure.” The time, duration, and type of episode, along with other notes, were also recorded. The study volunteers also reported information about their antiseizure medications, noting the type, dose, and reasons for discontinuing a regimen.
Patients were considered seizure-free if they did not have an episode for at least a year (or longer if their seizures were infrequent).
The study further showed that together, 63% of all participants experienced ongoing or even worsening seizures during the first year of therapy, whether or not they would eventually find relief.
Notably, those who had seizures only a few times per year prior to treatment were more likely to respond to medication than those who had them weekly. In addition, participants with a history of psychological disorders such as anxiety and depression were almost twice as likely to resist the drugs than those without such a history.
“Our results show that the best way to a new treatment plan is sometimes through making better use of the tools we already have instead of always searching for the next breakthrough drug,” said Dr French, who is also a member of NYU Langone’s Comprehensive Epilepsy Center.
The researchers next plan to more closely examine those who did not become seizure-free during the study period, says Dr French.
Dr French cautions that the investigation did not directly assess the role of regimen choice, dose, or side effects on the way patients responded to treatment, and it did not exclude participants who failed to adhere to their prescribed regimen.
A large Cleveland Clinic study has found that people with obesity and type 2 diabetes who undergo weight-loss surgery live longer and face fewer serious health problems compared with those treated with GLP-1 receptor agonist medicines alone.
Patients who had weight-loss surgery (also known as bariatric or metabolic surgery) lost more weight, achieved better blood sugar control, and relied less on diabetes and heart medications over 10 years. The research is published in Nature Medicine.
“Even with today’s best medicines, metabolic surgery offers unique and lasting benefits for people with obesity and diabetes,” said Ali Aminian, MD, director of Cleveland Clinic’s Bariatric & Metabolic Institute and primary investigator of the study. “The benefits we observed went beyond weight loss. Surgery was linked to fewer heart problems, less kidney disease, and even lower rates of diabetes-related eye damage.”
GLP-1 (glucagon-like peptide-1) receptor agonists are a class of medications widely used to treat type 2 diabetes and obesity and to reduce health risks. Both metabolic surgery and GLP-1 medicines improve cardiovascular health and metabolism.
The M6 study (Macrovascular and Microvascular Morbidity and Mortality after Metabolic Surgery versus Medicines) followed 3932 adults with diabetes and obesity who received care at Cleveland Clinic for up to 10 years. Among them, 1657 underwent metabolic surgery (including gastric bypass or sleeve gastrectomy), while 2275 were treated with GLP-1 medicines (including liraglutide, dulaglutide, exenatide, semaglutide, and tirzepatide).
At the end of the study, patients who had metabolic surgery had a:
32% lower risk of death
35% lower risk of major heart problems (such as heart attack, heart failure, or stroke)
47% lower risk of serious kidney disease
54% lower risk of diabetes-related eye damage (retinopathy)
On average, people who had metabolic surgery lost 21.6% of their body weight over 10 years, compared with 6.8% weight loss in people who took GLP-1 medicines. Hemoglobin A1c, a marker of average blood sugar, improved more with surgery (-0.86%) than with GLP-1 medicines (-0.23%). Patients in the surgery group also required fewer prescriptions for diabetes, blood pressure, and cholesterol.
“Even in the era of these powerful new drugs to treat obesity and diabetes, metabolic surgery may provide additional benefits, including a survival advantage,” said Steven Nissen, MD, Chief Academic Officer of the Heart, Vascular & Thoracic Institute at Cleveland Clinic and senior author of the study.
“Our findings indicate that surgery should remain an important treatment option for obesity and diabetes,” said Dr Aminian. “These long-term benefits are harder to achieve with GLP-1 medicines alone, as many patients stop using the medications over time.”
According to the authors, the study has some limitations. It was observational rather than a randomized comparison of drugs and surgery, and it did not focus exclusively on the newest and most effective GLP-1 medicines. The researchers note that future studies should directly compare surgery with newer GLP-1 therapies, such as semaglutide and tirzepatide, to further guide treatment decisions.
Common antidepressants, antibiotics and allergy drugs are being discharged into waterways, as conventional treatment fails to remove them
Photo by Myriam Zilles on Unsplash
Municipal wastewater treatment plants are ineffective at removing Prozac (fluoxetine) and other common pharmaceuticals in wastewater, causing the drugs to be discharged into lakes, rivers and streams where they pose a risk to aquatic organisms. Paulina Chaber-Jarlachowicz of the Institute of Environmental Protection – National Research Institute in Warsaw, Poland, and colleagues reported these findings in a new study published September 24, 2025 in the open-access journal PLOS One.
Most wastewater treatment plants break down organic compounds in wastewater using microbes, which are then removed as activated sludge. Existing research, however, suggests these methods do not remove pharmaceuticals effectively, causing them to be released into waterways. While some drugs do break down eventually, most persist in the environment, where they continue to be active, even at extremely low concentrations.
In the new study, researchers collected samples from six municipal wastewater treatment plants in Poland to investigate their ability to remove more than a dozen common pharmaceuticals. They measured the levels of drugs coming into the plant in the wastewater, determined how much is discharged to the environment in the treated water and sludge, and estimated the associated ecological risks.
The researchers found that all six wastewater treatment plants released pharmaceuticals into the environment. Only the pain reliever drugs naproxen (Aleve) and ketoprofen and the antihistamine salicylic acid were effectively removed during treatment.
For some pharmaceuticals, including the antidepressant fluoxetine (Prozac), the pain reliever diclofenac, and the anti-seizure drug carbamazepine, the treatment processes actually led to higher levels of the compounds in the discharged water than in the original wastewater. Fluoxetine and the allergy drug loratadine (Claritin) posed the greatest risk to aquatic organisms, due to their ability to disrupt hormone signaling and development at the levels seen in the treated water.
The new results add to the growing body of evidence demonstrating that conventional methods used by municipal wastewater treatment facilities are unable to remove many common drugs, making the plants a source of pharmaceutical pollution. These findings will lay the groundwork for further research into the inactivation of pharmaceutical compounds and their breakdown products in sewage and sludge.
The authors add: “The study’s findings demonstrated that municipal wastewater treatment facilities using conventional mechanical-biological processes (CAS) are ineffective at removing pharmaceuticals from wastewater. The annual emissions of pharmaceuticals to rivers from wastewater treatment plants in the study area amounted to at least 40Mg. Ketoprofen, sulfamethoxazole, carbamazepine and fluoxetine were identified as the primary contributors to the total mass load and emissions of pharmaceuticals.”
A study published in Nature Structural & Molecular Biology is the first time researchers have shown evidence that a single drug, already licensed for medical use, can stabilise nearly all mutated versions of a human protein, regardless of where the mutation is in the sequence.
The researchers engineered seven thousand versions of the vasopressin V2 receptor (V2R), which is critical for normal kidney function, creating all possible mutated variants in the lab. Faulty mutations in V2R prevent kidney cells from responding to the hormone vasopressin, leading to the inability to concentrate urine and resulting in excessive thirst and large volumes of dilute urine, causing nephrogenic diabetes insipidus (NDI), also known as arginine vasopressin resistance, a rare disease affecting roughly one in 25 000 people.
When they carried out further experiments looking specifically at mutations observed in patients, they found that the oral medicine tolvaptan, clinically-approved for other kidney conditions, restored receptor levels to near-normal for 87 per cent of destabilised mutations (60 out of 69 known disease-causing mutations, and 835 out of 965 predicted disease-causing mutations).
“Inside the cell, V2R travels through a tightly managed traffic system. Mutations cause a jam, so V2R never reaches the surface. Tolvaptan steadies the receptor for long enough to allow the cell’s quality control system to wave it through,” explains Dr. Taylor Mighell, first author of the study and postdoctoral researcher at the Centre for Genomic Regulation (CRG) in Barcelona.
The research group have previously shown that most mutations affect a protein’s function by altering its stability, making the whole structure wobblier than normal. According to the authors of the study, tolvaptan works regardless of where the mutation is because proteins switch between folded and unfolded forms. Most V2R mutations make the unfolded form more likely. When tolvaptan binds to V2R, it favours the folded form over the unfolded one.
The research is the first proof-of-principle study to demonstrate that a drug can act like a “nearly universal” pharmacological chaperone, meaning it can latch onto a protein and stabilise the structure regardless of where it’s mutated, in this case, in nearly nine out of ten cases.
The findings could help tackle a longstanding challenge in rare disease medicine. A rare disease is any disease affecting fewer than 1 in 2000 people. Though individual prevalence is low, rare diseases are a formidable challenge for global health because there are thousands of different types, meaning around 300 million people worldwide live with a rare condition.
Most rare diseases are caused by mutations in DNA. The same gene can be mutated in many ways, so patients with “the same” rare disease can have different mutations driving the condition. Because few individuals will have the same mutation, drug development is slow and commercially unattractive. Most treatments help manage symptoms rather than tackling the root cause of a rare disease.
Previous studies show that between 40 and 60% of rare-disease causing mutations affect a protein’s stability. If future studies confirm the rescued receptors work normally, the study offers a new roadmap for rare-disease drug development. Rather than look for a drug that targets a single mutation, researchers could instead look for one that targets stabilising an entire protein.
V2R is part of the human body’s largest family of receptors, also known as G-protein-coupled receptors (GPCRs). These roughly 800 genes are the targets of about a third of all approved drugs. Many rare and common diseases arise when GPCRs don’t fold or traffic correctly to the cell surface, even though their signalling parts are largely intact.
“If the behaviour we found holds for others members of GPCR family, drug developers could swap spending years of hunting for bespoke therapeutic molecules and try looking for general or universal pharmacological chaperones instead, greatly accelerating the drug development pipeline for many genetic diseases,” concludes ICREA Research Professor Ben Lehner, Group Leader at the Wellcome Sanger Institute (Hinxton, UK) and Centre for Genomic Regulation (Barcelona).
Translocations are chromosomal “cut and paste” errors that drive many lymphomas, a type of blood cancer and the sixth most common form of cancer overall. This includes mantle cell lymphoma, a rare but aggressive subtype diagnosed in about one in every 100 000 people each year.
Translocations are known to spark cancer by altering the activity of the genes near the breakpoints where chromosomes snap and rejoin. For example, a translocation can accidentally cut a gene in half, silencing its activity, or create new hybrid proteins that help promote cancer.
A study published today in Nucleic Acids Research shows a new way translocations promote cancer. The translocation most typically found in mantle cell lymphoma drags a powerful regulatory element into a new area of the human genome, where its new position allows it to boost the activity of not just one but 50 genes at once.
The discovery of this genome rewiring mechanism shows the traditional focus on the handful of genes at chromosomal breakpoints is too narrow. The study also greatly expands the list of potential drug targets for mantle cell lymphoma, for which there is no known cure.
“We did not expect to see a single translocation boosting the expression of almost 7% of all genes on a single chromosome. The ripples of disruption are much bigger than expected, and also identify new cancer driver genes, each of which represents a new potential therapeutic target,” says Dr. Renée Beekman, corresponding author of the study and researcher at the Centre for Genomic Regulation (CRG) in Barcelona.
In mantle cell lymphoma, a piece of chromosome 14 swaps places with a piece of chromosome 11. A gene regulatory element called the IGH enhancer, which normally boosts the activity of antibody production in healthy B cells, lands right beside CCND1, a gene which helps cells divide. The enhancer treats CCND1 as if it were a gene encoding for antibodies, boosting its activity and fuelling the disease.
Previous research has shown that boosting CCND1 expression alone is insufficient to kickstart the formation of mantle cell lymphoma. To understand why, the scientists first created translocations in cells in a dish. They used CRISPR to replicate the exact chromosome break seen in patients.
“We built a system to generate translocations in healthy B cells. Because these are engineered cells, we can carry out experiments that are technically or ethically unfeasible with patient tissues, making it a really useful early disease model,” explains Dr. Roser Zaurin, co-author of the study.
The experiments revealed that over fifty genes along the entire chromosome 11 were much more active after the translocation took place. The translocation affected gene activity across 50 million base pairs, a significantly larger space than previously thought.
How DNA folds inside the engineered cells revealed why the translocation affects so many genes at once. “DNA loops inside cells. It’s what brings two segments of DNA that are far away from each other in two-dimensional space closer together in three-dimensional space. The translocation drags the strong IGH enhancer into a preexisting loop, placing it in a privileged position of control, enabling it to have a widespread impact on dozens of genes at the same time,” explains Dr. Anna Oncins, first author of the study.
Intriguingly, most of the genes affected by the enhancer were not silent to begin with. The IGH enhancer simply dials their activity up. This biological nuance may explain why the same translocation can have different consequences in different cell types or stages of development. Only genes which were already active are boosted.
The findings could lead to new strategies for the early-stage detection of mantle cell lymphomas. “Because the enhancer mainly supercharges genes that were already active in the very first B cell that acquires the swap, epigenetic profiling of at-risk cells could spot dangerous combinations before a mantle cell lymphoma appears,” explains Dr. Beekman.
The authors of the study next plan on studying exactly how the newly identified genes contribute to the initiation and progression of lymphoma. Understanding and eventually interrupting the effects of the chromosomal translocation could yield broader, more durable therapies for mantle-cell lymphoma and other types of cancers driven by chromosome swaps.
This image shows a coronal section through the mouse brain after stroke and neural stem cell transplantation. The dashed circle indicates the stroke area. The neurite projections of the transplanted human cells are stained in dark brown. Neurites extend locally into the cortex (CX) but also via the corpus callosum (CC) into the other brain hemisphere. (Image: UZH)
One in four adults suffer a stroke in their lifetime, leaving around half of them with residual damage such as paralysis or speech impairment because internal bleeding or a lack of oxygen supply kill brain cells irreversibly. No therapies currently exist to repair this kind of damage. “That’s why it is essential to pursue new therapeutic approaches to potential brain regeneration after diseases or accidents,” says Christian Tackenberg, the Scientific Head of Division in the Neurodegeneration Group at the University of Zurich (UZH) Institute for Regenerative Medicine.
Neural stem cells have the potential to regenerate brain tissue, as a team led by Tackenberg and postdoctoral researcher Rebecca Weber has now compellingly shown in two studies that were conducted in collaboration with a group headed by Ruslan Rust from the University of Southern California. “Our findings show that neural stem cells not only form new neurons, but also induce other regeneration processes,” Tackenberg says.
The studies employed human neural stem cells, from which different cell types of the nervous system can form. The stem cells were derived from induced pluripotent stem cells, which in turn can be manufactured from normal human somatic cells. For their investigation, the researchers induced a permanent stroke in mice, the characteristics of which closely resemble manifestation of stroke in humans. The animals were genetically modified so that they would not reject the human stem cells.
One week after stroke induction, the research team transplanted neural stem cells into the injured brain region and observed subsequent developments using a variety of imaging and biochemical methods. “We found that the stem cells survived for the full analysis period of five weeks and that most of them transformed into neurons, which actually even communicated with the already existing brain cells,” Tackenberg says.
Brain regenerates itself
The researchers also found other markers of regeneration: new formation of blood vessels, an attenuation of inflammatory response processes and improved blood-brain barrier integrity. “Our analysis goes far beyond the scope of other studies, which focused on the immediate effects right after transplantation,” Tackenberg explains. Fortunately, stem cell transplantation in mice also reversed motor impairments caused by stroke. Proof of that was delivered in part by an AI-assisted mouse gait analysis.
Clinical application moving closer to reality
Human neural stem cells in culture. Cell nuclei are stained in blue, the neural stem cell-specific filament protein Nestin is shown in green, and the neural stem cell transcription factor Sox1 in red. (Image: UZH)
When he was designing the studies, Tackenberg already had his sights set on clinical applications in humans. That’s why, for example, the stem cells were manufactured without the use of reagents derived from animals. The Zurich-based research team developed a defined protocol for that purpose in collaboration with the Center for iPS Cell Research and Application (CiRA) at Kyoto University. This is important for potential therapeutic applications in humans. Another new insight discovered was that stem cell transplantation works better when it is performed not immediately after a stroke but a week later, as the second study verified. In the clinical setting, that time window could greatly facilitate therapy preparation and implementation.
Despite the encouraging results of the studies, Tackenberg warns that there is still work to be done. “We need to minimize risks and simplify a potential application in humans,” he says. Tackenberg’s group, again in collaboration with Ruslan Rust, is currently working on a kind of safety switch system that prevents uncontrolled growth of stem cells in the brain. Delivery of stem cells through endovascular injection, which would be much more practicable than a brain graft, is also under development. Initial clinical trials using induced stem cells to treat Parkinson’s disease in humans are already underway in Japan, Tackenberg reports. “Stroke could be one of the next diseases for which a clinical trial becomes possible.”
A new study from researchers at The University of Texas MD Anderson Cancer Center shows that the glucose-fructose mix found in sugary drinks directly fuels metastasis in preclinical models of advanced colorectal cancer. The study was published in Nature Metabolism.
A research team led by Jihye Yun, PhD, assistant professor of Genetics, studied how sugary drinks may affect late-stage colorectal cancer. Using laboratory cancer models, they compared the effects of the glucose-fructose mix found in most sugary drinks with those of glucose or fructose alone. Only the sugar mix made cancer cells more mobile, leading to faster spread to the liver – the most common site of colorectal cancer metastasis.
The sugar mix activated an enzyme called sorbitol dehydrogenase (SORD), which boosts glucose metabolism and triggers the cholesterol pathway, ultimately driving metastasis. This is the same pathway targeted by statins, common heart drugs that inhibit cholesterol production. Blocking SORD slowed metastasis, even with the sugar mix present. These findings suggest that targeting SORD could also offer an opportunity to block metastasis.
“Our findings highlight that daily diet matters not only for cancer risk but also for how the disease progresses once it has developed,” Yun said. “While these findings need further investigation, they suggest that reducing sugary drinks, targeting SORD or repurposing statins may benefit patients with colorectal cancer.”
The Yun Laboratory is interested in studying how diet affects the intestine and cancer development, and they have made important discoveries on the impacts of sugary drinks on colorectal cancer.
Sugar has long been indirectly linked to an increase in cancer risk through obesity. However, a previous study by Yun’s lab challenged that view, showing that even moderate intake of sugary drinks directly fuelled tumour growth in early-stage colorectal cancer, independent of obesity. The current study was done to determine how sugary drinks may impact later-stage disease.
While this study needs further clinical investigation, the results suggest that reducing sugary drinks and targeting the SORD enzyme may offer opportunities to reduce colorectal cancer metastasis. Additional studies are warranted to confirm these results outside of preclinical models.
Further, Yun explained it may be worthwhile to consider revisions to current dietary recommendations to reduce sugary drink consumption in this patient population. To meet nutritional needs, many patients with cancer are encouraged to have nutritional supplement drinks and concentrated juices that contain high glucose and fructose content.
