New research published in Allergyindicates that certain environmental exposures may affect a child’s risk of developing atopic eczema, a condition characterised by dry, itchy, and inflamed skin. In other words, although some people may be genetically predisposed to eczema, certain environmental factors may increase or decrease that risk.
For the study, investigators analysed data from 16 European studies to test for interactions between the 24 most significant eczema-associated genetic variants and 18 early-life environmental factors. They applied their findings to an additional 10 studies and used lab modelling tests to assess their results.
The first analysis (including 25 339 individuals) showed suggestive evidence for interaction between 7 environmental factors (antibiotic use, cat ownership, dog ownership, breastfeeding, elder sibling, smoking, and washing practices) and at least one established genetic variant for eczema, with 14 interactions in total.
In the additional analysis (254 532 individuals), dog exposure interacted with a particular genetic risk variant on chromosome 5, near the gene that codes for the interleukin-7 receptor, a protein involved in immune cell function. Lab modelling tests showed that this variant affects expression of interleukin-7 receptor in human skin cells and that dog exposure modifies the genetic effect of this variant on the development of eczema, essentially providing a protective effect by suppressing skin inflammation.
Additional studies are needed to explore these lab findings and the other potential interactions identified in the first analysis.
“Our research aims to answer some of the most difficult questions that I am asked in clinic: ‘Why does my child have eczema?’ and ‘What can I do to help protect my baby?’ We know that genetic make-up affects a child’s risk of developing eczema and previous studies have shown that owning a pet dog may be protective, but this is the first study to show how this may occur at a molecular level,” said corresponding author Sara J. Brown, MD, PhD, FRCPE, of the University of Edinburgh. “More work is needed, but our findings mean we have a chance to intervene in the rise of allergic disease, to protect future generations.”
Looking to nature for answers to complex questions can reveal new and unprecedented results that can even affect cells on molecular levels. For instance, human cells oxidise glucose to produce ATP (adenosine triphosphate), an energy source necessary for life.
Cancer cells produce ATP through glycolysis, which does not utilise oxygen even under conditions where oxygen is present, and convert glucose into pyruvic acid and lactic acid. This method of producing ATP, known as the Warburg effect, is considered inefficient, thus raising questions as to why cancer cells choose this energy pathway to fuel their proliferation and survival.
In search for this energy catalyst, Associate Professor Akiko Kojima-Yuasa’s team at Osaka Metropolitan University’s Graduate School of Human Life and Ecology analysed the cinnamic acid ester ethyl p-methoxycinnamate, a main component of kencur ginger, and its mechanism of action. In previous research, the team discovered that ethyl p-methoxycinnamate has inhibitory effects on cancer cells. Furthering their study, the acid ester was administered to Ehrlich ascites tumour cells to assess which component of the cancer cells’ energy pathway was being affected.
Results revealed that the acid ester inhibits ATP production by disrupting de novo fatty acid synthesis and lipid metabolism, rather than through glycolysis as commonly theorised. Further, the researchers discovered acid ester-induced inhibition triggered increased glycolysis, which acted as a possible survival mechanism in the cells. This adaptability was theorised to be attributed to ethyl p-methoxycinnamate’s inability to induce cell death.
“These findings not only provide new insights that supplement and expand the theory of the Warburg effect, which can be considered the starting point of cancer metabolism research, but are also expected to lead to the discovery of new therapeutic targets and the development of new treatment methods,” stated Professor Kojima-Yuasa.
Authors of a recent Lancet report argue that obesity should not just be seen as a risk factor for other diseases – but in some cases, should be seen as a disease itself. The position could change how we treat obesity globally. In the first of this two-part Spotlight series, we break down the debate around the issue, and its implications for health policy.
In 1990, just 2% of all young people around the world aged 5 to 24 were living with obesity. By 2021, this figure had more than tripled to over 6%. This is according to a recent study, which relied on Body Mass Index (BMI) data from 180 countries and territories around the world. It estimates that the rise in obesity among children and young people will only continue in the coming decades.
South Africa certainly isn’t immune to the crisis. A survey conducted in 2021/2022 found that 16% of all children aged 6 to 18 were “severely overweight”. Meanwhile, World Health Organization (WHO) data suggests that about 30% of all adults in South Africa are living with obesity, meaning a BMI of over 30, which is almost double the global level.
BMI, which simply looks at a person’s weight in relation to their height, is a crude measure of obesity. For instance, a person may have a high BMI simply because they have a lot of muscle rather than fat. But while it is agreed that BMI is a flawed indicator at the individual level, many experts recommend using it as a rough proxy for “health risk at a population level”.
For instance, a study which collected data on nearly three million people found that those who had very high BMI levels were, on average, more likely to die at an early age. The study also found that this was true of people with very low BMI levels (those who were underweight). In this context, the above figures paint a concerning picture.
Given the rising rates, experts argue that we need health systems to be able to track and respond to obesity urgently. But, according to a Lancet Commission published in January, health systems around the world may struggle to do this, because of a failure to accurately conceptualise and measure what obesity actually is.
The Lancet commission was developed by 58 experts from different medical specialties and though it has been the subject of debate, it has since been widely endorsed as a new way to understand obesity. Spotlight takes a look at what it concluded.
Delaying treatment for no reason
Obesity is often regarded as a risk factor for other diseases, for instance, type 2 diabetes. But according to the commission, there are certain cases in which obesity is not just a risk factor, but a disease itself – one that should be immediately treated.
One of the reasons for this is that obesity not only contributes to the emergence of other conditions but sometimes leads to clinical symptoms directly. For example, the cartilage that protects the joints in a person’s knees can sometimes become eroded when adults carry too much weight. In this case, a person could suffer from joint pain, stiffness and reduced mobility where obesity is clearly the cause.
Take another example. If fat deposits build up in the abdomen, this may limit how much the lungs can expand, causing breathlessness. Similarly, a build-up of fat around the neck can narrow a person’s upper airways, which can cause sleep apnoea.
Thus, obesity is not simply something which increases the risk of developing a separate disease in the future – but something which can directly (and presently) affect the functioning of organs.
More broadly, the commission argues that by hindering a person’s “mobility, balance and range of motion” obesity can in certain cases “restrict routine activities of daily living”. In these instances, obesity is a disease by definition, according to the commission. This is given that it defines disease as a “harmful deviation from the normal structural or functional state of an organism, associated with specific signs and symptoms and limitations of daily activities”.
But why does this conceptual debate matter?
Because at present, people often have to wait for other diseases to crop up before insurers or public health systems cover them for weight loss drugs or bariatric surgery – a procedure to help with weight loss and improve obesity-related health conditions. And when they do cover these services, it is often only after severe delay. Because obesity is only considered to be a risk factor, it isn’t typically treated with the same urgency as life-threatening diseases, according to the authors of the commission.
Professor Frances Rubino, the lead author of the commission, details how this problem manifests in the healthcare system.
“I’ve been doing bariatric surgery for 25 years in four different countries; in America, Italy, France and the UK,” he tells Spotlight, “In all of those countries, to meet the criteria for surgery people very often have to undergo six to 12 months of weight monitoring before their surgery is covered. So systematically you delay treatment”.
He continues: “Someone who has clinical obesity and has heart failure as a result of it is waiting for a year for what reason? That condition will only worsen and if the patient is still alive, the treatment [is] going to cost the same amount to the payer but it’s going to be less effective.”
Can’t people just diet?
One of the reasons that some academics have historically been reluctant to classify obesity as a disease is because of a fear that this may reduce people’s agency – instead of taking proactive steps to diet and exercise, people with obesity may simply view themselves as afflicted by a disease.
The belief that people with obesity can simply diet their way out of their situation is in fact partially why Rubino’s patients were forced to wait long periods of time before receiving bariatric surgery.
Rubino explains: “In America, many private payers [i.e. medical insurance schemes] have required weight monitoring programmes, where patients do nothing else other than see a dietician for 12 months, and if they skip one appointment, they have to start all over again. I think that in some cases, this has been misguided by the idea that you want to see if obesity can be reversed by somebody going on a diet.”
This, according to him, is a “misconception”, arguing that if someone faces such severe levels of obesity that they require surgery, diet is unlikely to offer a solution.
Indeed, research has shown that it’s very rare for people with obesity to lose large amounts of weight quickly without surgery or medication. For instance, a study on over 176 000 patients in the UK found that among men with “simply obesity” or a BMI of 30-34.9, only 1 in 210 were able to achieve a “normal” weight level within a year. Among men with morbid obesity or BMI of 35 or more, the chance was less than 1 than in 1000. Chances for women were roughly twice as good as men’s – so still exceedingly small.
Thus, if someone is severely obese and their excess weight is causing life-threatening symptoms, putting them on a diet for a year is unlikely to result in the urgent changes that may be required for them to get better. In fact, Rubino argues that they may simply die of their condition in the interim.
Taking a medical approach more quickly is easier now than ever before due to the regulatory approval of GLP-1 agonists like semaglutide and tirzepatide – Spotlight previously reported on the availability of these new diabetes and weight loss medicines in South Africa. An article by WHO officials from December states that because of the approval of these medicines “[h]ealth systems across the globe now may be able to offer a treatment response integrated with lifestyle changes that opens the possibility of an end to the obesity pandemic”.
Not all people with obesity are ill
There is a more scientific argument against categorising obesity as a disease. This is that while obesity can sometimes result in the negative health symptoms discussed above (like respiratory issues or reduced mobility) it doesn’t always do this.
In fact, the commission acknowledges that some people with obesity “appear to be able to live a relatively healthy life for many years, or even a lifetime”. One of the reasons for this is that excess fat may be stored in areas that don’t surround vital organs. For instance, if fat is stored in the limbs, hips, or buttocks, then this may cause less harm than if it is stored in the stomach.
Since obesity doesn’t always cause health problems, it isn’t always a disease. In order to deal with this conceptual hurdle, the commission classifies obesity into two categories – clinical and preclinical obesity.
If a person has pre-clinical obesity, this means they have a lot of excess fat, but no obvious health problems that have emerged as a result. In this case, obesity is not classified as a disease, though it may still increase the chance of future health problems (depending on a range of factors, like family history).
For a person to have clinical obesity, they must have a lot of excess fat as well as health problems that have already been directly caused by this. It is this that the commission defines as a disease.
This classification system, according to Rubino, ensures not only that we urgently treat people living with clinical obesity, but also that we don’t overtreat people – since if a person falls into the pre-clinically obese group, then they may not need treatment.
But if we’re going to treat clinical obesity as a disease, we’ll need clear methods of diagnosing people. Since BMI is deeply flawed and provides little information about whether a person is ill at the individual level, health systems will need something else. In part 2 of this Spotlight special series, we’ll discuss the options offered by the commission, and how this all relates to the situation in South Africa.
Scanning electron micrograph of a T cell lymphocyte. Credit: NIH / NIAID
A study initiated by a University of Arizona Comprehensive Cancer Center physician-scientist has for the first time defined how loss of the Y chromosome in male immune cells negatively affects immune system function. The findings, published in Nature, may explain why loss of Y is associated with lower cancer survival rates.
In males, each cell in the body usually contains one X and one Y chromosome. “Loss of Y” is a common, nonhereditary genetic change in men in which an immune cell in the blood loses its Y chromosome. It is often associated with aging. Loss of Y has been linked to increased mortality from carcinomas for many years, though no one knew why.
This study is the first to identify and define the relationship between loss of Y in white blood cells, immune cells and tumours, providing insights as to why men with loss of Y have increased cancer risks and poorer outcomes.
“These findings represent a big step forward in our understanding of why men with loss of Y in their blood cells have a higher mortality from cancer. It turns out it’s because these cells make the immune system infiltrating the cancer less effective,” said Dan Theodorescu, MD, PhD, director of the Cancer Center and a professor in the College of Medicine – Tucson.
“We hope this provides a solid lead and framework for the nascent Y chromosome field to pursue so we can collectively better understand all the possible biological implications of this finding and how to use them to develop more effective approaches in prevention, treatment resulting in higher survival rates for patients.”
The research team discovered that loss of the Y chromosome – previously identified in malignant epithelial cells by the Theodorescu lab – also occurred in nearby noncancerous tissues, including connective tissue and immune cells.
Most notably, the team found that this chromosomal loss in helper and cytotoxic T cells, which are responsible for attacking cancer cells, was associated with a reduced ability to kill those cancerous cells. The findings suggest a mechanism by which tumours may evade immune detection and suppression.
Finally, the research team found that loss of Y in epithelial cells, combined with loss of Y in T cells, resulted in more aggressive cancers and lower survival rates in patients.
“The study has potential implications for current immunotherapies, including CAR T therapy,” Theodorescu said. “Further research is clearly needed but perhaps immunotherapies using cells from a patient’s immune system could be screened for loss of Y before being used in treatment.”
A breakthrough study from the Hebrew University of Jerusalem, published this week in the prestigious journal PNAS (Proceedings of the National Academy of Sciences USA), reveals a previously unknown peripheral mechanism by which paracetamol relieves pain.
The study was led by Prof Alexander Binshtok from the Hebrew University’s Faculty of Medicine and Center for Brain Sciences (ELSC) and Prof Avi Priel from its School of Pharmacy. Together, they uncovered a surprising new way that paracetamol, one of the world’s most common painkillers, actually works.
For decades, scientists believed that paracetamol relieved pain by working only in the brain and spinal cord. But this new research shows that the drug also works outside the brain, in the nerves that first detect pain.
Their discovery centres on a substance called AM404, which the body makes after taking paracetamol. The team found that AM404 is produced right in the pain-sensing nerve endings – and that it works by shutting off specific channels (called sodium channels) that help transmit pain signals. By blocking these channels, AM404 stops the pain message before it even starts.
“This is the first time we’ve shown that AM404 works directly on the nerves outside the brain,” said Prof Binshtok. “It changes our entire understanding of how paracetamol fights pain.”
This breakthrough could also lead to new types of painkillers. Because AM404 targets only the nerves that carry pain, it may avoid the numbness, muscle weakness, and side effects that come with traditional local anaesthetics.
“If we can develop new drugs based on AM404, we might finally have pain treatments that are highly effective but also safer and more precise,” added Prof Priel.
