Category: The Conversation – UK

Source: The Conversation – UK – By Laurenz Casser, Leverhulme Trust Early Career Fellow, University of Sheffield

At some point between conception and early childhood, pain makes its debut. But when exactly that happens remains one of medicine’s most challenging questions.

Some have claimed that foetuses as young as twelve weeks can already be seen wincing in agony, while others have flat-out denied that even infants show any true signs of pain until long after birth.

New research from University College London offers fresh insights into this puzzle. By mapping the development of pain-processing networks in the brain – what researchers call the “pain connectome” – scientists have begun to trace exactly when and how our capacity for pain emerges. What they discovered challenges simple answers about when pain “begins”.

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The researchers used advanced brain imaging to compare the neural networks of foetuses and infants with those of adults, tracking how different components of pain processing mature over time. Until about 32 weeks after conception, all pain-related brain networks remain significantly underdeveloped compared with adult brains. But then development accelerates dramatically.

The sensory aspects of pain – the basic detection of harmful stimuli – mature first, becoming functional around 34 to 36 weeks of pregnancy. The emotional components that make pain distressing follow shortly after, developing between 36 and 38 weeks. However, the cognitive centres responsible for consciously interpreting and evaluating pain lag far behind, and remain largely immature by the time of birth, about 40 weeks after conception.

This staged development suggests that while late-term foetuses and newborns can detect and respond to harmful stimuli, they probably experience pain very differently from older children and adults. Most significantly, newborns probably can’t consciously evaluate their pain – they can’t form the thought: “This hurts and it’s bad!”

A history of changing views

These findings represent the latest chapter in a long-running scientific debate that has swung dramatically over the centuries, often with profound consequences for medical practice.

For most physiologists in the 18th and 19th centuries, the perceived delicacy of the infant’s body meant that it must be exquisitely sensitive to pain, so much so that some have had their doubts if infants ever felt anything else. Birth, in particular, was imagined to be an extremely painful event for a newborn.

However, advances in embryology during the 1870s reversed this thinking. As scientists discovered that infant brains and nervous systems were far less developed than adult versions, many began questioning whether babies could truly feel pain at all. If the neural machinery wasn’t fully formed, how could genuine pain experiences exist?

This scepticism had troubling practical consequences. For nearly a century, many doctors performed surgery on infants without anaesthesia, convinced that their patients were essentially immune to suffering. The practice continued well into the 1980s in some medical centres.

Towards the end of the 20th century, public outrage about the medical treatment of infants and new scientific results turned the tables yet again. It was found that newborns exhibited many of the signs (neurological, physiological and behavioural) of pain after all, and that, if anything, pain in infants had probably been underestimated.

The ambiguous brain

The reason why there has been endless disagreement about infant pain is that we cannot access their experiences directly.

Sure, we can observe their behaviour and study their brains, but these are not the same thing. Pain is an experience, something that’s felt in the privacy of a person’s own mind, and that’s inaccessible to anyone but the person whose pain it is.

Of course, pain experiences are typically accompanied by telltale signs: be it the retraction of a body part from a sharp object or the increased activity of certain brain regions. Those we can measure. But the trouble is that no one behaviour or brain event is ever unambiguous.

The fact that an infant pulls back their hand from a pin prick may mean that it experiences the pricking as painful, but it may also just be an unconscious reflex. Similarly, the fact that the brain is simultaneously showing pain-related activity may be a sign of pain, but it may also be that the processing unfolds entirely unconsciously. We simply don’t know.

Perhaps the infant knows. But even if they do, they can’t tell us about their experiences yet, and until they can, scientists are left guessing. Fortunately, their guesses are becoming increasingly well informed, but for now, that is all they can be – guesses.

What would it take to get certainty? Well, it would require an explanation that connects our brains and behaviour to our conscious experiences. But so far, no scientifically respectable explanation of this kind has been forthcoming.

Laurenz Casser receives funding from the Leverhulme Trust.

– ref. When do we first feel pain? – https://theconversation.com/when-do-we-first-feel-pain-259588

Source: The Conversation – UK – By Justin Stebbing, Professor of Biomedical Sciences, Anglia Ruskin University

In November 1922, archaeologist Howard Carter peered through a small hole into the sealed tomb of King Tutankhamun. When asked if he could see anything, he replied: “Yes, wonderful things.” Within months, however, Carter’s financial backer Lord Carnarvon was dead from a mysterious illness. Over the following years, several other members of the excavation team would meet similar fates, fuelling legends of the “pharaoh’s curse” that have captivated the public imagination for just over a century.

For decades, these mysterious deaths were attributed to supernatural forces. But modern science has revealed a more likely culprit: a toxic fungus known as Aspergillus flavus. Now, in an unexpected twist, this same deadly organism is being transformed into a powerful new weapon in the fight against cancer.

Aspergillus flavus is a common mould found in soil, decaying vegetation and stored grains. It is infamous for its ability to survive in harsh environments, including the sealed chambers of ancient tombs, where it can lie dormant for thousands of years.

When disturbed, the fungus releases spores that can cause severe respiratory infections, particularly in people with weakened immune systems. This may explain the so-called “curse” of King Tutankhamun and similar incidents, such as the deaths of several scientists who entered the tomb of Casimir IV in Poland in the 1970s. In both cases, investigations later found that A flavus was present, and its toxins were probably responsible for the illnesses and deaths.

Despite its deadly reputation, Aspergillus flavus is now at the centre of a remarkable scientific finding. Researchers at the University of Pennsylvania have discovered that this fungus produces a unique class of molecules with the potential to fight cancer.

These molecules belong to a group called ribosomally synthesised and post-translationally modified peptides, or RiPPs. RiPPs are made by the ribosome – the cell’s protein factory – and are later chemically altered to enhance their function.

While thousands of RiPPs have been identified in bacteria, only a handful have been found in fungi – until now.

The process of finding these fungal RiPPs was far from simple. The research team screened a dozen different strains or types of aspergillus, searching for chemical clues that might indicate the presence of these promising molecules. Aspergillus flavus quickly stood out as a prime candidate.

The researchers compared the chemicals from different fungal strains to known RiPP compounds and found promising matches. To confirm their discovery, they switched off the relevant genes and, sure enough, the target chemicals vanished, proving they had found the source.

Purifying these chemicals proved to be a significant challenge. However, this complexity is also what gives fungal RiPPs their remarkable biological activity.

The team eventually succeeded in isolating four different RiPPs from Aspergillus flavus. These molecules shared a unique structure of interlocking rings, a feature that had never been described before. The researchers named these new compounds “asperigimycins”, after the fungus in which they were found.

The next step was to test these asperigimycins against human cancer cells. In some cases, they stopped the growth of cancer cells, suggesting that asperigimycins could one day become a new treatment for certain types of cancer.

The team also worked out how these chemicals get inside cancer cells. This discovery is significant because many chemicals, like asperigimycins, have medicinal properties but struggle to enter cells in large enough quantities to be useful. Knowing that particular fats (lipids) can enhance this process gives scientists a new tool for drug development.

Further experiments revealed that asperigimycins probably disrupt the process of cell division in cancer cells. Cancer cells divide uncontrollably, and these compounds appear to block the formation of microtubules, the scaffolding inside cells that are essential for cell division.

Tremendous untapped potential

This disruption is specific to certain types of cells, so this may in turn reduce the risk of side-effects. But the discovery of asperigimycins is just the beginning. The researchers also identified similar clusters of genes in other fungi, suggesting that many more fungal RiPPs remain to be discovered.

Almost all the fungal RiPPs found so far have strong biological activity, making this an area with tremendous untapped potential. The next step is to test asperigimycins in other systems and models, with the hope of eventually moving to human clinical trials. If successful, these molecules could join the ranks of other fungal-derived medicines, such as penicillin, which revolutionised modern medicine.

The story of Aspergillus flavus is a powerful example of how nature can be both a source of danger and a wellspring of healing. For centuries, this fungus was feared as a silent killer lurking in ancient tombs, responsible for mysterious deaths and the legend of the pharaoh’s curse. Today, scientists are turning that fear into hope, harnessing the same deadly spores to create life-saving medicines.

This transformation, from curse to cure, highlights the importance of continued exploration and innovation in the natural world. Nature has in fact provided us with an incredible pharmacy, filled with compounds that can heal as well as harm. It is up to scientists and engineers to uncover these secrets, using the latest technologies to identify, modify and test new molecules for their potential to treat disease.

The discovery of asperigimycins is a reminder that even the most unlikely sources – such as a toxic tomb fungus – can hold the key to revolutionary new treatments. As researchers continue to explore the hidden world of fungi, who knows what other medical breakthroughs may lie just beneath the surface?

Justin Stebbing does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.

– ref. Toxic fungus from King Tutankhamun’s tomb yields cancer-fighting compounds – new study – https://theconversation.com/toxic-fungus-from-king-tutankhamuns-tomb-yields-cancer-fighting-compounds-new-study-259706