THE GLASGOW INSIGHT INTO SCIENCE AND TECHNOLOGY
Drugdiscovery:naturalproducts
Nakedmolerat’sagingsecrets
Neurofeedbackforbraindisorders
Nanoparticles:quantumimmunehelpers
PasteurvsKoch:scientificrivalry
EDITORIALNOTE
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I ¸hk² k²²½eI Õe b®kg Û½ a ²®ga²b®d f h¸ ¸«kc² f® I Õk¸h fkÔe fea¸½®e a®¸kce² ec«a²²kg a dkÔe®²e a®®aÛ f ²cke¸kfkc ¸hee²I Õk¸h Natalia Bicharska exploring drug discovery from natural products, Caitlin Cosgrove uncovering the secrets of the naked mole rat, as well as Lama Jamaleddine with a feature on Neurofeedback, Veneta Salyahetdinova looking at the nanoscale world with quantum dots, and Cameron McKeddie revisiting the history rivalry of Pasteur and Koch in groundbreaking microbiology discovery.
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Conen
ART I C LES
Reviving Natural Products
Drug Discovery
- Natalia Blicharska
Naked mole rats: What's their secret to healthy aging?
- Caitlin Cosgrove
Neurofeedback: Paving the path for future treatment of neurocognitive and mood disorders
- Lama Jamaleddine
An invisible hero - nanoparticles as an emerging quantum helper of the immune system
- Veneta Salyahetdinova
Animosity as Motivation - Lessons from the Rivalry Between Pasteur and Koch
- Cameron McKeddie
SNI P P ETS
Nuclear Fusion: The future of sustainable electricity?
- Christopher McQueen Chemistry AI
Contact explosives : chemistry is a blast! Physics
- Chris Riggs
Mathematics
A strange world of numbers
- K Sridevi
Mindful Machines: The underlying mechanisms of Advanced Artificial Intelligence
- Miya Han
The Climate Crisis is a Health Emergency Other
- Ella Spencer
Stuck in the lab: why gender bias lingers in research
- Hazel Imrie
REVIVING NATURAL PRODUCTS DRUG DISCOVERY
By Natalia Blicharska
Natalia investigates the role of natural products in the future of pharmaceutical research and contemplates, in the light of advancing technologies, whether anything remains to be discovered.
Natural remedies sourced from plants, fungi, or microbes, have played an important role in medicine for centuries. This comes as no surprise, considering their vast phytochemical diversity with demonstrated antioxidant, anti-inflammatory, or antibacterial effects, among others. However, what may be surprising, especially in light of the medicinal cornucopia that are our modern pharmacies, is the fact that natural products continue to play an important role in modern drug discovery.
Gone are the days of herbal preparations, teas, and concoctions,whichhavenowbeen all but replaced in Western countriesbysinglemoleculedrugs, manyofwhichhavenaturalorigins (nearly 42% of all drugs released since1981,infact!).
The use of natural products in medicine has vastly evolved over the centuries, especially following advancements in chemistry during the 19th Century. Pharmacognosy, simply known as drug discovery from natural sources, has produced numerous valuable medicines including aspirin, penicillin, and taxol. With everimproving advancements in technologies such as microelectron diffraction (MicroED) and genome mining, natural products continue to reinvent themselves and prove they still have much to offer modern drug discovery programs.
Benefits of Natural Products in Drug Discovery
The many significant benefits of using natural products in drug discovery reach far beyond well-documented traditional use. Phytochemicals, secondary metabolites, and other molecules produced by plants, fungi, and microbes offer a highly diverse array of complex structures that can be exploited in the development of new drugs.
defenses, that can be exploited in drug development. After all, why would a plant, fungus, or microbe produce a molecule (an energetically expensive endeavor) only for it to have no vital use?
Why the Decline in Natural Product (NP) Drug Discovery?
Despite their many advantages to pharmaceutical research — not least of which include their long-established history of use, vast chemical diversity, and many pharmaceutical successes — pharmaceutical companies began to lose interest in NP drug discovery, choosing instead to focus on combinatorial chemistry, rational drug design, and High-throughput-screening as the future. This decision to forego NP research altogether may have been brought about by the inherent challenges plaguing NP drug discovery.
It's no secret that NP research is highly complex, time-consuming, and expensive. The laborious process of preparing extracts, followed by repeated chromatography separations until pure compounds are isolated, challenges in determining a molecule’s chemical structure, and difficulties in the synthetic synthesis of complex bioactive molecules, isnotforthefaintofheart
Ranging from polyketides to flavonoids, and terpenes to alkaloids,thediversityofchemical compounds found in natural products far surpasses chemical libraries generated by pharmaceuticalcompanies.
And this can inspire both novel drug leads or serve as scaffolds for new drug design. More importantly, since these molecules have evolved within living organisms, they inherently possess diverse bioactivities, such as chemical
Different extraction techniques, temperatures, and storage conditions can collectively impact the stability of isolated products. And even if researchers are investigating brand-new, natural products, they risk re-discovering molecules that have already been isolated.
If, undeterred by these challenges, scientists do go on to investigate NPs and identify potential ‘hits’, the difficulty in replicating results during scale-up does not make it feasible for pharmaceutical companies to pursue identified leads.
This is particularly true when working with plant extracts, whose composition is never the same and varies with a plant’s biogeographical origins, the seasons, and other environmental factors. The high likelihood of cross-contamination with other microbes or fungi presents further challenges. More importantly, navigating the patenting legalities also proves to be a hindrance to pharmaceutical companies, who have little incentive to investigate natural products that cannot be patented. After all, one would certainly hope for a good return after investing £1 million pounds and 10 years of work.
Despite these drawbacks, there is a resurgence of interest in NPs because current (synthetic) drug discovery programs have demonstrated limited success. In fact, combinatorial chemistry research has produced only 3 European Union/Food and Drug Administration approveddrugsworldwide.
Not only are current drug discovery programmes not working, the advent of technologies such as MicroED are addressing the limitations previously experienced in structure elucidation of natural compounds, while genome mining is opening up new avenues for exploration, proving that yet again, natural products have much to offer.
Advancements in Technology
Traditional spectroscopic techniques such as infrared spectroscopy, mass spectroscopy, and nuclear magnetic resonance (NMR) are important tools in natural product research. Afterall, to develop a pharmaceutical drug, one must know what the molecule looks like in terms of its structure. X-Ray crystallography has served as the gold standard in structure elucidation, unambiguously determining absolute stereochemistry of molecules. However, these techniques have several limitations. For instance, despite its usefulness in determining the arrangement of bonds in a molecule, NMR is often limited in its ability to assign the absolute stereochemistryofchiralcenters, while
X-Ray crystallography requires high quality crystals for analysis. The crystallization of NP molecules is a slow and laborious process and often impossible due to the flexible nature of such molecules and the small quantities isolated via traditional methods. Also, the successful growth of a crystal does not always guarantee successful analysis. These issues are being addressed with the advancement of techniques such as MicroED, a technology similar to X-Ray crystallography, but that is capable of determining the structures of compounds using crystals (approx. 100 nm) significantly smaller than those needed for X-Ray crystallography.
It does so by subjecting small quantities of a sample to electron diffraction under a Transmission Electron Microscope (TEM) in diffraction mode, whilst being rotated on a stage. A camera captures this data as a movie, generatingafractionpatternfrom eachframewhichcanbeanalyzed by X-Ray crystallography software to reveal the sample’s chemicalstructure.
Applications of this technology have already been demonstrated, with several research groups successfully resolving the absolute stereochemistry of different compounds. The routine usage of MicroED will revolutionise NP drug discovery by overcoming the limitations of previous spectroscopic techniques whilst rapidly identifying and elucidating the chemical structures (including those from mixtures such as extracts).
The advent of genome mining is further expanding the resources available for investigation. Genome mining, as the name would suggest, is the process of searching the genomes of organisms, such as bacteria, to identify biosynthetic gene clusters (BGCs). These BGCs are clusters of genes that encode enzymes involved in common metabolic pathways, including those that are critical in the production of compounds such as antibiotics. A once untapped resource, genome mining is becoming increasingly important in NP drug discovery, because many organisms (whose genomes we have mapped, and believed to have thoroughly investigated) have the genetic capabilities of producing many more compounds than are currently known, that is, they possess BGCs that are not being expressed.
More importantly, by manipulating the expression/activation of different enzymes within BGCs, scientists can produce new derivativesofmoleculeswhichmay haveinterestingbioactivities.
Resurging interest in NP drug discovery is a hopeful sign for the future. Afterall, the challenges facing NP research do not relate to a lack of study material, rather the speed with which one can discover NPs. It is well understood that the vast majority of the world’s plants have never been investigated for medicinal potential. And as if there isn’t already enough to explore, genome mining is further opening new avenues for investigation. Not only are new species of microorganisms being identified (containing BGCs capable of producing novel molecules), previously studied organisms, such as Streptomyces coelicolor A3(2), are now understood to possess more BGCs than their metabolites, revealing there is still much to discover. Medicinal plants and NPs have proven themselves time and again to be an untapped, and ever-expanding reservoir for drug discovery. Like the carpet bag carried by Mary Poppins, they are yet to yieldalltheirsecrets.
Can uncovering the secrets of the naked mole rat’s resistance to ageing help humans on their quest to eternal youth?
Hairless, wrinkled and nearly blind — the naked mole rat does not exactly coincide with our conventional ideas of what youthfulness and beauty look like, yet this strange little creature appears to completely defy ageing. These hardy rodents can live over 30 years, five times longer than expected based on their body size. As well as their impressive longevity, naked mole rats are also resistant to many age-related diseases including cancer and dementia. So, forget looking to your favourite celebrity for their latest skin care routine or diet that promises to be the secret to healthy ageing and look to the age-defying wonder that is the naked mole rat.
Appearance and Social Structure
The naked mole rat is not familiar to most but if you grew up in the early 2000s it’s likely that the mention of the animal will bring back memories of a popular little character from the well-known Disney channel show Kim Possible; Rufus. Rufus was the infamous crime fighting naked mole rat sidekick of Kim Possible and Ron Stoppable. Considered a fan favourite, this naked mole rat created an enduring fond memory of the creatures for kids of the 2000s. However, fans of Rufus may be a little taken aback by his true appearance that wasn’t quite captured by the cute cartoon…
The body of the naked mole rat is pink, wrinkled and (almost) hairless. They are about 3-4 inches long and have prominent, yellowish chisel-like teeth that allow them to dig their underground tunnels where they spend most of their lives. Over the course of evolution, spending extensive periods in darkness has led to the regression of their eyes. They have become small and poorly developed for sight and they are covered with a layer of skin to protect them from dirt while digging. They instead rely on their well-developed other senses, such as touch and smell to navigate the dark. They have specialised sensory hairs, known as vibrissae, sparsely distributed across their body (hence the almost hairless) which can detect even the slightest vibrations and movement in their surroundings.
As if their appearance and choice of habitat wasn’t weird enough, they also display social behaviour that is considered unusual for a mammal. Naked mole rats behave more like a
honeybee hive or an ant colony than a group of mammals. They display what is known as eusocial behaviour. They live in colonies dominated by a queen who is served by all the other members of the group. Like the queen bee, she’s the only female allowed to reproduce. The queen ages even more slowly than her male counterparts and continues to reproducerightuntiltheendofherlife.
Unique Resistance to Ageing astheGompertzlaw or the “law of mortality” which states that as an individual gets older, the likelihood of dying increases atanacceleratingrate.
damage becomes less efficient. At a cellular level, cells become less able to divide and function properly, known as cellular senescence Ultimately, at the level of organs, this leads to dysfunction and increased susceptibility to diseases like cancer, cardiovascular disease, and dementia. Yet, amidst this universal narrative of ageing, the naked mole rat is an exception and offers an invaluable opportunity to uncover mechanisms to resist ageing.
Even considering their bizarre appearance and social structure, the most striking thing about the naked mole rat remains their longevityandresistanceto age-relateddiseases. The oldest naked mole rat known to humans, Joe, turned 39 years old in 2021 and showed remarkably little signs of ageing. Naked mole rats defy what is known
The law is generally true for all mammals after adulthood, for example in humans the risk of death doubles every 8 years but in naked mole rats their risk of death does not increase as they get older. In fact, even in their older years, cardiac function is maintained, they show signs of neurogenesis (the generation of new neurons in the brain) and show no signs of cancer. So, good news for fans of Rufus, he is likely still alive and fighting crime with the same gusto as in his younger years however for Kim and Ron…the effects of ageing may soon be putting a stop to their crime fighting days. If we were to revisit Kim and Ron now, they might have started getting a few more grey hairs and wrinkles and running around fighting evil all day may exhaust them a lot more than before. So, what is happening in ageing that is causing this? At its core, ageing involves a gradual decline in the body's ability to repair and maintain itself. At a molecular level our DNA, our genetic code, accumulates damage withage and ourmechanismsforrepairing this
Unfortunately, naked mole rats haven’t quite divulged all their ageing secrets just yet, but scientists have managed to reveal some pretty exciting stuff. In 2023, one
particularly groundbreaking finding came from the University of Rochester. Scientists successfully introduced a gene from the naked mole rat into mice which significantly improved their lifespan and health span. The gene is responsible for making high molecular weight hyaluronic acid (HMW-HA). The naked mole rat produces HMW-HA of a far greater mass (6.1 MDa) than humans (1 MDa) which is thought to be a key driver of its protective effects.
A prior study showed that HMW-HA protected naked mole rat cells, as well as mouse and human cells, fromdamageanddeath.
The protective effect was linked to its interaction with the receptor, CD44, which is associated with the p53 pathway, a molecular pathway important in tumour suppression. Demonstrating that the benefits of HMW-HA can be transferred between mammals suggests that, in the future, this benefit could also be transferred to humans.
senescent cells. This adaptation is thought to allow them to harness the benefits of senescence — preventingdamagedcells fromdividinguncontrollably andpotentiallyleadingto cancer.
The accumulation of DNA damage is a significant hallmark of ageing and it appears that naked mole rats are able to reduce this damage by having very active and efficient mechanisms for DNA repair Again, this may be linked to the tumour suppressor protein p53, which has a 10 times longer half life (the time it takes for the concentration of a substance to decrease by half) in naked mole rats compared to humans and mice.
Another important hallmark of ageing already discussed is cellular senescence
Surprisingly, researchers found that naked mole rats do actually undergo cellular senescence, however, they exhibit heightened resistance to its negative effects by suppressing the metabolic activity of
Scientists have also found that their underground, low-oxygen environment has allowed them to evolve distinct cardiometabolic adaptations that maycontributetotheirgoodhealth.
Their hearts show remarkable resistance to ischemia-reperfusion injury, which is damage caused by the sudden return of blood flow after a period of oxygen deprivation. They also have a unique metabolic profile with elevated glycogen for energy during low oxygen conditions and reduced levels of succinate, which limits damage to DNA and proteins from reactive oxygen species (reactive molecules that contain oxygen). Figuring out how to use these insights to tackle ageing in humans will be the work of future scientists.
Conclusion
If you weren’t already a fan of the naked mole rat from watching the loveable Rufus on television then I hope you have now been convinced that what naked mole rats lack in looks they more than make up for in their fascinating biology. Understanding the ways that these weird and wonderful creatures resist ageing remains an exciting area of research with no doubt, many extraordinary
secrets still to be revealed. While the naked mole rat may not conform to the conventional standards of beauty, itsunconventionalbiologycouldbethekey tocombatingage-relateddiseasesandextendinghumanlifespan.
We are witnessing a revolution in the field of neuroscience, more specifically in the field of neuroimaging, which is advancing at a rapid rate. Neurofeedback is key evidence of this advancement in neuroimaging methods and their potential therapeutic applications. So what is neurofeedback?
Neurofeedback is where measurements of a patient’s neural signals are continuously presented back to the patient, with the goal of enabling self-regulation of brain activity and behaviour.
Initially, neurofeedback used electroencephalography (EEG) as its medium. However, over the past 10 years neurofeedback has been increasingly used with fMRI (functional magnetic resonance imaging) and fNIRS (functional near infrared spectroscopy), which has allowed neurofeedback to detect signals within deep brain structures and be less affected by background noise, hence improving its accuracy and resolution. Before delving into neurofeedback, let us dissect what EEG, fMRI and fNIRS are.
fMRI
Firstly, fMRI is a neuroimaging technique that measures brain activity in a specific region as both blood flow and oxygen levels increase in thatregion.
When brain regions are activated, the increase in blood flow exceeds the increase in oxygen consumption, leading to a relative increase in oxygenated blood to deoxygenated blood in regions of higher brain activity, generating a Blood Oxygen Level Dependent (BOLD) fMRI signal EEG measures electrical activity of the brain through the use of electrodes that detect electrical impulses acrossthescalp
fNIRS
Finally, fNIRS uses similar techniques to fMRI, focusingonchangesinbloodoxygenationlevelsto detectbrainactivity.
The difference between them is that fMRI relies on magnetic fields while fNIRS relies on near-infrared light spectroscopy and is less affected by participant motion.
Howdoesneurofeedbackwork?astep-by-stepguide
1. We define a region of interest in the brain either anatomically or functionally using fMRI evidence. There are multiple ways to define a region of interest in the brain and these could be reliant on i) multi-slice, ii) functional volume, iii) anatomical volume, and iv) surface volume. In neurofeedback studies, multi-slice and functional volume are the more common approaches taken. The multi-slice approach measures activity in multiple slices of the brain region, whereas the functional volume approach focuses on defining a brain region with a specific function e.g., sensory processing.
Figure 1: Images show how the region of interest is defined; the first outlines using a multi-slice approach while the second uses a functional volume approach with a BOLD signal displayed in the graph. The graph displays the time (in seconds) in the x-axis while the y-axis displays the hemodynamic response function representing the BOLD signal. The green line is the BOLD signal before it has been corrected for artifact signals like breathing.
2. Specific measurements are taken from brain slices in the specified region of interest, including the BOLD signal.
3. The BOLD signal is corrected for physiological artefacts such as breathing and motion to allow for a more accurate BOLD signal which is directly relative to the neurofeedback task.
4. The participant performs a neurofeedback task and their BOLD signal is analysed in real time. The feedback training can be either continuous, where feedback is continuously presented to participants the whole time that participants are asked to regulate their brain activity, or intermittent, where feedback is only given after an extended period.
5. When the cognitive task and neurofeedback training are complete, the effects of neurofeedback on behaviour and functional activity are analysed using software like Turbo Brain Voyager. This analysis can be based primarily on i) BOLD signal changes in a single region of interest, ii) BOLD activity in multiple regions of interest, or iii) multi-voxel pattern analysis of a single region of interest. A voxel is a three-dimensional square chunk of brain tissue that can be identified visually in a brain image scan.
Figure 2: A visual summary of the neurofeedback process and the BOLD response.
Where has neurofeedback been applied clinically and what are its benefits and drawbacks?
Recent studies have focused on using neurofeedback as a means of emotional regulation by targeting the amygdala and brain areas itconnectsto
These studies investigated patients diagnosed with post-traumatic stress disorder (PTSD), anxiety disorders and major depressive disorder andhadpromisingresults.
For example, Zotev and colleagues (2018) embarked on a study combining fMRI, EEG and neurofeedback training of amygdala activity in PTSD patients. In the study, patients learned to upregulate BOLD activity in the left amygdala using a continuousfMRI neurofeedback cognitive task involving autobiographical happy memories EEG and fMRI recordings then followed these neurofeedback sessions in the amygdala and dorsolateral prefrontal cortex, as well as an assessment of the behavioral effects of the neurofeedback training on PTSD symptoms.
Following neurofeedback sessions, there was a significant decrease in PTSD symptoms and an increase in connectivity between DLPFC and amygdala.
However, the effect on amygdala activity was less clear, possibly due to the already hyperactive state of the amygdala in PTSD patients which can make neurofeedback more difficult.
Zotev and colleagues (2020) later used the same methodology to investigate emotion regulation training in patients with major depressive disorder (MDD). MDD patients have reduced connectivity in amygdala and related networks compared to PTSD patients
In this study, fMRI- and EEG-neurofeedback significantly enhanced the connectivity between the left amygdala and left rostral anterior cingulate cortex, which have a key role in the regulation of emotional processing. Another rewarding result was the improvement in depressive symptoms following neurofeedback sessions.
These studies open a window for research tackling deficiencies in amygdala prefrontal functional connectivity among PTSD and MDD patientsusingneurofeedback.
Particularly promising is the overall reduction in PTSD and depressive symptoms, increased happiness and the neurophysiological specificity i.e., only the targeted regions in the brain were affected by neurofeedback.
However, these studies could adopt certain improvements including larger sample sizes, controlling for participation motivation, behavioral, and external stimuli effects, and finally using double blinded trials, where neither the participants nor the researchers know which group is receiving the neurofeedback and which are the control group.
The benefits of using real time-fMRI neurofeedback are related to its excellent spatial resolution and extensive access to deep structures within the brain. However, a salient drawback is the issue of delayed BOLD signal due to dilated bloodvesselsorhighmetabolicrate.
Although there are growing numbers of promising studies with novel approaches including fNIRS-FMRI neurofeedback and virtual reality-EEG neurofeedback, significantly more research is needed in the field of neurofeedback before we can make any conclusions. We can, however, deduce that neurofeedback could be used as a therapeutic method for patients battling neurocognitive and mood disorders. Perhaps, we could also see neurofeedback as a means of treating other disorders, like epilepsy, traumatic brain injury, andevenheadaches,giventherisingevidence.
VN I SIBLE HERO asanemergingquantumhelper oftheimmunesystem
Nanoparticles (NPs) nanoworld of our cells because of biocompatibilitywiththecellularenvironment
Quantum dots (QDs) that have become a very interesting branch of research in recent years.
They are composed of a core — most often a heavy metal, such as cadmium selenide, indium arsenide or lead selenide — and an outer shell which serves a protective role against the metal’s toxicity.
Other important components of QDs are the ligands attached to the outer shell; it is these organic surface molecules which enable NPs to serve their function. These ligands, often biopolymers or small molecules, serve as a biological layer which facilitates interaction between the QD and its biological target. QDs are foreign to the human body, and so their presence could trigger harmful and unwanted immune responses. This means that during their development, they must be carefully screened to make sure this is avoided. QDs of the same size but with larger ligands have also been shown to be lesseffective in being taken up into cells, meaning they cannot reach their biological targets, further supporting the importance of biolayer composition. Target specificity is an important consideration in the development of any type of medicine and QDs are no different. Selection of the appropriate ligand plays a crucial role in limiting non-specific interactions with other proteins. This improves both the effectiveness of the QD in its intended function and avoids unwanted responses.
QDs’ superior fluorescence lifetime properties make them very photostable, and they can therefore maintain their fluorescence signal for longer durations; this in turn results in a precise final image of the QDs’ surroundings. They have wide excitation, but narrow emission spectra, meaning that they can be excited by a wide range of wavelengths while emitting within a limited window. These characteristics make them an interesting alternative to the organic dyes used today. Further adding to their suitability for
QDs effectively label haematological cells, bone marrow and umbilical cord cells, and An important retained by the cells post . This continue to exert their effects or carry out within the differentiated cells or even modulate the cell’s fate. Apart from producing images of cellular organelles or structures, QDs have been used for tracking extracellular vesicles, which compose the main part of intracellular communication. These sacs, filled with proteins, carry an important function. For instance, the hormoneinsulin is stored and secreted by secretory vesicles. If we not only togethighresolution
More importantly, thesenanocrystals show potential to assist the immune system by being involved in drug-delivery systems, vaccines or becoming the better alternative to antibiotics.
The better a virus’ mode of invasion into the host cell is understood, and its replication within it, the better we can produce vaccines against it.
Moreover, QDs could be designed to combat viral particles by interacting with them through appropriate ligands. To fight against such a small assembly of molecules, scientists need a weapon just as small to interact with the virus on a molecular level, and QDs seem to be the perfect fit for this role.
Furthermore, theyarenotonlyeffectiveagainst viruses,butNPsmayalsoserveasnanobactericides, combatting multi-drugresistantpathogens through their interactionswithreceptors on the surface of the bacterial cell membrane. In doing so, they can ultimately interferewiththebacterium’smetabolicpathways, killing the pathogen.
QDs could also become an integral part of drug-delivery with their exceptional potential to deliver drugs to a specific site. For example, the anti-cancer treatment doxorubicin is more successful in reducing tumour size when, delivered by a QD compared to its
However, as exciting as it is that quantum dots could in fact become an integral part of science and medicine, ongoing research is required to better understand their drawbacks. For example, metal toxicity, potential non-specific interactions and the development of bacterial resistance toward NP treatment all present possible challenges and further development to address them is needed.
Perhaps one way to prevent the latter concern could be not to overuse NPs in order to avoid repeating the history of antibiotics misuse.
Once these challenges are eliminated, NPs could be able to fulfil theirfullpotentialandcontributeimmenselytoscience.
-Lessons from the Rivalry Between PasteurandKoch
The founding fathers of microbiolo�� set immense milestones for medical innovation, but their fierce competition threatened many lives in pursuit of lifesaving discoveries.
Dear reader, I ask you to bear with me as I glance on a troubling time from our very recent history. I invite you now to release a sigh of exasperation as I reveal this introduction concerns the COVID-19 pandemic. Many of us will recall with a healthy degree of distaste the COVID-19 lockdown. Though posing a great burden on our lives, this public health-oriented response and the introduction of vaccines curbed the spread of the virus responsible for disease and allowed us to emerge bleary-eyed into the world, anxious to enter our nearest Greggs and smile as we feared no longer the spread of contagion through our coveted pork pastries.
Many will take for granted our understanding of COVID-19 being caused by a coronavirus, just as the common cold is caused by a rhinovirus or influenza by its own eponymous virus. However, just over 100 years ago during the 19th Century, doctors believed tuberculosis was either inherited or a form of cancer and that infectious diarrhoea was caused by pungent smells. Thanks to the efforts of two men these beliefs changed, and it became apparent that illness was caused by microscopic germs (microbes), kickstarting the field of study called microbiology. Considered now as the fathers of microbiology, the Frenchman Louis Pasteur and the German Robert Koch revolutionised diagnosis, treatment and even prevention of disease and changed the world.
Students of microbiology and medicine are doubtless inspired by their valiant efforts, though in this case the adage “Never meet your heroes” rings true even if those heroes are long since dead. What I will now illustrate to you is how the world-changing research conducted by
these men was underpinned by a venomous and unrelenting rivalry that, despite motivating both scientists to strive for greater achievements, ultimately threatened their scientific integrity, personal relationships and eventhelivesofthosetheysoughttosave.
But first, let’s set the scene.
Europe at War
As the conclusion of the 19th Century drew near, war struck Europe Emperor Napoleon III of France, seeking a fraction of the glory so readily attributed to his namesake, declared war on the newly formed North German Confederation, marking the beginning of the Franco-Prussian War of 1870. The sentiment for conflict was festering for decades, spurred by a shifting power balance in continental Europe following the monumental Prussian victory over Austria, directly threatening French superiority established almost 100 years prior by Napoleon I. The outcome was a swift and humiliating defeat for the numerically superior French (the war spanning no more than seven months), plagued by logistical shortcomings, communication failures and an outdated command model. With the French military routed, Paris bombarded, the emperor exiled and the territories of Alsace and Lorraine ceded to the Germans, the Second French empire collapsed and was formally dissolved by September 1870. To further rub salt in the wound, the formation of the German Empire was proclaimed in the palace of Versailles, the historic seat of French royal authority. Pasteur and Koch were men grown by the time of the war, being aged 47 and 26, respectively. Both were staunch patriots and had personal stakes in the war, Pasteur’s only son being a soldier and Koch volunteering as an army surgeon on account of his background in medicine.
The flames of war clung to these two healers, igniting a fiery ambition to make monumental advances in infectious disease research for the betterment of humanity or, perhaps cynically, to prove their country’s superiorityovertheother.
Early Work
A decade following the armistice resolving the Franco-Prussian War, both Pasteur and Koch were accomplished microbiologists. Pasteur had definitively disproved spontaneous generation (the theory that life can arise spontaneously from inorganic matter) and Koch developed sterile culture techniques on solid agar to better distinguish individual microorganisms of interest from vast mixtures of bacterial cells. Both men made great contributions to dispelling the misapprehension that disease is caused by foul odours, revealing that microscopic organisms are instead responsible. Each shared a common interest in anthrax, the disease that plagued rural France and Germany, annihilating herds of cattle and sheep alike and compromising both nations’ rural productivity.
Koch had spent the years 1873-1876 observing infected sheep blood under his microscope and noted small rod-shaped cells. He named the bacteria Bacillus anthracis and went on to discover its ability to produce spores explaining how “cursed fields” could kill livestock years after any disease was present. Building on this discovery, Pasteur conducted a successful trial of his anthrax vaccine in Spring 1881, preserving the lives of 70infectedsheep.
First Blood
Come Summer 1881, in recognition of their contributions to industry and public health, both were invited to the Seventh International Medical Congress in London where they met for the first time. Their meeting was arranged by Joseph Lister, the British surgeon who, inspired by Pasteur’s work on spontaneous generation, introduced the concept of aseptic technique to surgical practices in Britain. Thanks to Lister, you’d be hard-pressed to find any iPhones in an operating theatre.
Following the presentation of his anthrax vaccination findings, Pasteur attended Koch’s demonstration on sterile cell culture. Pasteur complimented him, remarking
FCIest un grand progrès, MonsieurG
“It’s a big step forward, sir”
Despite this, Koch held bitterness for Pasteur’s unwillingness to formally acknowledge his seminal work on anthrax, mentioning him only in a footnote of one of his publications. As a result, he and his colleagues proceeded to draw first blood, critiquing Pasteur publicly by labelling his findings erroneous and inconsequential.
Open Hostility
At the fourth International Congress of Hygiene and Demography in Geneva in September 1882, the pair would clash publicly. Earlier that year, Koch made the groundbreaking discovery of Mycobacterium tuberculosis, the bacterium responsible for tuberculosis, which was then the single biggest infectious cause of death and today is second only to COVID19inmortality.
Anticipating praise and recognition, Koch was unpleasantly surprised by Pasteur’s lecture on vaccination where the speaker made a public rebuttal to Koch’s accusations following the London congress of 1881. Tensions flared when Pasteur’s innocuous mention of Koch’s work,
FRecueil allemandG
“German collection”
was mistranslated as FOrgeuil allemandG
“German arrogance”
Koch interrupted, protesting furiously, making for an awkward scene as Pasteur and other French-speakers were bewildered by this disproportionate reaction.
Once again, Koch in his literature dismissed Pasteur’s vaccination data as useless and his opinions irrelevant given his lack of medical credentials. This inflamed the public spat and intense animosity that would persist for the remainderoftheirlives.
Scientific One-upmanship
By Winter of 1884 Koch had isolated Vibrio cholerae in Kolkata, India. This proved cholera, another epidemic killer, to be caused by germs from contaminated water rather than miasma as was believed at the time. Marking Koch’s second substantial advance in infectious disease, Pasteur felt the pressure.
Joseph Meister, a nine-year-old boy from the recently annexed region of Alsace, was presented to Pasteur by a panicked mother, the child bitten by a rabid dog no more than 48 hours prior. As many will be aware, rabies is transmitted by animals infected with the rabies lyssavirus and following an incubation period ranging from a few days to over a year there is a near 100% probability of death. Aware of death’s certainty, Pasteur tested his incomplete vaccineonJosephwithlittleregardforsafety.
The result, published in 1885, was that young Joseph Meister miraculously survived, and further trials proved the vaccine’s efficacy in humans. Donations poured in from around the world to fund Pasteur’s work, and in the years following the Pasteur Institute in Paris was opened. Koch, undoubtedly influenced by Pasteur’s international acclaim and the founding of the Pasteur Institute, resolved to make an even more ambitious accomplishment. As of then, he had identified the causes of anthrax, tuberculosis and cholera, but had yet to succeed in producing a cure for any of these diseases. Come the turn of 1890, this all changed. That year he trialled tuberculin, his own cure for tuberculosis, in humans. And it wasadisaster.
While initial tests in guinea pigs showed improvements in symptoms, his rush to conduct human trials proved the drug to be more lethal than the disease itself Public outrage and peer scrutiny both called for Koch to disclose the tuberculin formula, though these calls were refused. Despite this, one year later Koch was appointed the director for the Institute for Infectious Disease in Berlin As of 1942, this was renamed the Robert Koch Institute in his honour, yet would never attain the legendary status of the Pasteur Institute.
Take-home Message
Both Pasteur and Koch made tremendous advances in medical science, though their motivations should be considered. Products of the cutthroat politics of academia and harbouring xenophobic attitudes from the Franco-Prussian War, many of these advances were made in response to foreign developments in infectious disease, calling into question the altruistic nature of the discoveries.
Due to the intensity of competition between the two scientists, both denounced the other publicly to undermine their authority while also ignoring the meaningful advances made by their opponent.
Ultimately, human lives were put at risk for the sake of ego, and in the case of tuberculin many were claimed as a result.
While we should take inspiration from the advances made by both pioneers of germ theory and vaccination, let’s not ignore the danger of personal pride and reckless ambition. By all means, strive to be the greatest in your field, but consider that greatness is also judged by the strength of one’scharacter.
Featured Snippets Featured Snippets
NUCLEARFUSION NUCLEARFUSION NUCLEARFUSION
With the ongoing climate crisis, sustainable electricity is of major significance to the world. The current main contender for green energy comes in the form of renewables such as wind and solar, however, these suffer from reliability issues, as we can’t control when it’s windy or sunny.
Current nuclear power generation relies on nuclear fission, the splitting of heavy atoms, which results in radioactive by-products that remain dangerous to humans and the environment for thousands of years. Fortunately, another aspect of nuclear reactions may provide a solution to all of these problems, and it relies on the physics at the heart of stars.
When atoms of the lightest element, hydrogen, are forced together under immense temperature and pressure, they begin to fuse together to form helium in a process known as nuclear fusion. This process releases vast amounts of green energyandisthepowersourceof allstars.
Although challenging, controlled fusion reactions have been possible for decades, so why don’t we have commercial fusion reactors? The main culprit is the ratio of the energy produced by the reaction to the amount of energy required to start it, known as the gain. If the gain is less than one, the reaction consumes more energy than it generates, which doesn’t make for a very good power source.
This issue was overcome for the first time on 5th December 2022, when the National Ignition Facility (NIF) in California fired 2.05 million joules of laser energy at a small spherical capsule containing fusion fuel at its centre. The result was 3.15 million joules of energy from nuclear fusion, providing a gain of over 1.5. This technique works by using lasers to rapidly vaporise material on the capsule’s surface. Thanks to Newton’s third law — that every reaction has an equal and opposite reaction — a shockwave is driven into the centre of the target, compressing the fuel enough for fusion to begin. This experiment has since been repeated with even larger gains.
While a huge achievement, there is still a long way to go before commercial nuclear fusion is available. For instance, the lasers used in the experiment required much more energy to charge than was released, so the development of more efficient lasers is crucial. Even so, with renewed funding for NIF and the promise of other fusion technologies which use strong magnetic fields to heat plasmas, it may only be a matter of time before nuclear fusion is powering the world.
Chemistryisablast!
Contact explosives are a realm of chemistry I find fascinating. What could be more appealing to a budding chemist than something that explodes seemingly just by looking at it?
A contact explosive is a chemical which requires only a small quantity of energy to explode violently. They differ from normal explosives in that simple heating, friction, or exposure to alpha particles or magnetic fields can cause detonation.
A classic example is nitrogen triiodide. The element nitrogen ‘wants’ to be in the stable diatomic form, N2. As a result, nitrogen-based compounds can be very unstable, easily breaking apart and releasing N2 in the process.
Nitrogen triiodide (NI3) has three large iodine atoms, all bonded to one small nitrogen atom. Nitrogen itself has five electrons, three of which are used in bonding to the iodine atoms. The remaining pair of electrons repel the iodine atoms, forcing nitrogen triiodide into a congested pyramidal shape. The nitrogen-iodine bonds are under tremendous strain and easily snap, releasing a cloud of nitrogen and iodine gas.
This reaction, the decomposition of nitrogen triiodide, is particularly beautiful to behold, and one I have used when teaching chemical bonding to my pupils.
To prepare this reaction requires the use of concentrated ammonia solution and iodine. Adding them together then leaving them out to dry yields a dark purple, almost black solid material. Gently stroking it with a feather results in an incredibly loud bang, a thick cloud of purple smoke, and (in my experience at least) a shrieking technician. Failure to properly clean your experimental area afterwards will lead to numerous smaller, but just as loud, random detonations occurring throughout the rest of the day as the remains continue to pop.
Contact explosives can be formed accidentally too. Picric acid — historically used as a component in biological sample preservatives and medical kits — becomes very unstable when dried out. When clearing out old specimens, one university found a jar containing a frog, pickled using picric acid. The solvent had evaporated, leaving the frog coated in picric acid crystals. One slight knock could have resulted in the detonation of the amphibian and the destruction of a large portion of the lab. Museums and high school labs have even called in bomb disposal teams to remove specimens
number
Integers, as we studied in primary school, are sequentially arranged as -1 ,0, 1, 2. As we moved to higher grades, we encountered rational numbers (fractions). Then, as we zoomed into a sequence of rational numbers, we encountered numbers that cannot be expressed as a fraction (irrational). This collection of rational and irrational numbers creates the number system we all know: real numbers, also known as Archimedean numbers
Mathematicians also came up with another way to fill in the gaps between the rational numbers: p-adicnumbers!
“P-adic numbers are an infinite collection of numbers associated with a unique prime number ‘p’: the 2-adics, 3-adics, and so on. Just as one can arrange the real numbers based on the distance between them, p-adic numbers are arranged using the p-adic distance.”
The p-adic distance between two numbers and is defined as the inverse of the distance between real numbers x and y. For example, in the case of 3-adics, the numbers 1 and 4 are at a distance apart, whereas 1 and 10 are at a distance apart. Hence, the numbers that are closer to each other differ by a large power of 3.
This scheme is illustrated in the figure below, where we see that numbers 1 and 10 are in the same circle, emphasising that they are closer than 1 and 4. This idea is counterintuitive to what we have seen in real numbers, but it follows all the rules of the number system.
This scheme is illustrated in the figure below, where we see that numbers 1 and 10 are in the same circle, emphasising that they are closer than 1 and 4. This idea is counterintuitive to what we have seen in real numbers, but it follows all the rules of the number system.
An illustration showing the arrangement of numbers from 0-26 based on their 3-adic distance.
Superficially one might wonder what good would such a scheme of ordering numbers provide. But p-adics are highly celebrated in the mathematical society for solving various polynomial equations. For example, finding out if the polynomial has rational solutions is hard, however, it is relatively easy to find p-adic solutions.
The main motivation of this article is to let the readers know that there exists a different world of number systems that is counterintuitive from what we have learnt in high school. This Snippet itself does not explain p-adics completely. To learn more about them, you can listen to the 2018 Field Medal lecture by Peter Scholze of the University of Bonn. This abstract concept is still being explored across various fields, including quantumcommunicationtheoryinphysics
Mindful Machines:
The underlying mechanisms of Advanced Artificial Intelligence
Imagine a world where machines possess the ability to process and discriminate information the way the human brain does. This curiosity has sparked the formation of artificial neural networks (ANNs). ANNs are computing systems inspired by the structure and functioning of the human brain. This programming enables algorithms to learn patterns and make predictions based on data. ANNs provide expansive computational possibilities, now serving as the interface between neuroscience and computer science.
ANNs aim to achieve a concept known as deep learning, a type of machine learning that leverages ANNs to solve complex tasks, mirroring the cognitive capabilities of the human brain. The term “deep” refers to the use of densely connected layers of nodes, which parallels the architecture of the network of neurons in the human brain. Such structure has enabled machines to automatically learn hierarchical representations of data, allowing comprehension of intricate patterns and features.
ANNs are tremendously complicated as they can perform millions of calculations both at the network and single node level. Data moves through each layer of nodes in one direction. A single node can be connected to several nodes in the layer beneath it, from which it receives data, and several nodes in the layer above it, to which it sends data.
For every incoming or outgoing connection it makes, a node will be given a number, which is referred to as a weight. Weights indicate the strength and direction of the connection. Once a node is activated it gets a piece of information from each connection it has, and each piece is multiplied by the associated weight. After this, all these multiplied values are added up, and the result is a single number. If the number is below a threshold value, the node passes no data to the next layer of nodes.
“ However, if the number exceeds the threshold value the node ‘fires’, meaning its number is sent along all outgoing connections. Essentially, activated networks process information by taking an input, adjusting it based on importance, and combining it to produce the most appropriate output.
The ultimate objective of this programming is to train ANN models that discern intricate patterns. Subsequently, machines undergo a training phase, in which the weights of the networks are adjusted
TheClimateCrisis
BY ELLA SPENCER
EDITED BY HAZEL IMRIE
IS A
HealthEmergency
COPY-EDITED BY RACHEL SHANNON
In May this year, the World Meteorological Organisation (WMO) reported that there is a 98% likelihood that over the next five years temperatures will be the hottest on record, driven by both greenhouse gases and a naturally occurring El Niño event. This will mark the first time that temperatures exceed the 1.5 degrees-above pre-industrial levels specified in the Paris Agreement in 2015. This agreement, signed by 196 nations, denoted a commitment to limit the temperature increase in an effort to prevent more severe consequences of climate change. As the threat of global warming persists, it is more important than ever that we prepare for the effectsofthisclimatecrisis.
A recent report by the United Nations’ International Panel on Climate Change (IPCC) highlighted the effects of climate change on health, which include approximately 250,000 additional deaths per year from malnutrition, malaria, diarrhoea and heat stress[3].
Air pollution is also linked to increased respiratory illnesses, chronic diseases and cancer. Finally, the IPCC reportdrawsattentiontothe increasesinmentalhealth disorders due to climate change. Rising temperatures are linked to poor mental health, increased hospital admissions for psychiatric disorders and disrupted sleep, and psychological reactions to climate change suchasclimateanxietyareemerging.
Further, a systematic review published in Nature reported that almost two thirds of known human infectious diseases can be aggravated by climate change. For example, rising temperatures and earlier springs give mosquitos more opportunities to reproduce and expand their habitats, thus spreading mosquito-borne diseases such as malaria and dengue virus to new regions. Water-borne diseases such as cholera are likely to rise because of disrupted sanitation systems and flooding. There is also anincreasedriskof zoonoticdiseases:illnessescarriedbyanimalsthathave previously not infected humans but may begin to ‘spill over’andinfectthem.
As with most health emergencies, low- and middleincome countries will be most affected by these challenges.Whilstmitigationofclimatechange,namely through the reduction of fossil fuel use, remains vital, adaptation to these new challenges is called for. This could be achieved through increased funding for healthcare, international vaccine programmes and surveillance of emerging diseases. Importantly, taking a ‘One Health’ approach to research, involving collaboration across disciplines and recognising the intersection between people, animals and environmental health, should remain a priority both in fundingandpolicy.
in thelab: WHY
ender Bias G
LINGERS IN RESEARCH
A gender bias in research, whereby women are underrepresented in studies, has been established for some time now. In 1993, the National Institute for Health (NIH) released their Revitalization Act, demanding that women be represented in clinical studies
Despite a subsequent increase in inclusivity, reports estimate that women still only make up around 30% of participants in early clinical trialsforpharmaceuticals.
For example, in 2019, the prophylactic anti-HIV drug Descovy was approved for use, but only for those assigned male at birth due to the exclusion of women from clinical trials. Similarly, heart attack symptoms, e.g., chest pain, are derived from studies in men. As a result, there have been several cases of delayed treatment in women presenting with unrecognised (female)heartattacksymptoms.
These figures are even worse for preclinical studies investigating cells and rodents, where 8 out of 10 studies were shown to have a male bias. But why is this?
The oldest argument for the exclusion of females in studies is that the menstrual cycle causes variation between individuals that must be controlled for. When controlling for additional factors, data analysis becomes complicated and more participants are needed. However, evidence suggests that interindividual variation is actually greater in males, perhaps due to stronger sexual selection (competition),thusthisargumentholdslittletraction
The second justification given is the risk to fertility This fear was fuelled by the 1950s thalidomide scandal, where the prescription of a morning sickness drug to pregnant women resulted in birth defects in their unborn children. However, excluding women from studies simply limits our understanding of drug safety andpotentiateshealthcareinequalities.
There is increasing support to look beyond the gender binary, and to include transgender and non-binary individuals in research. While gender identity is now understood as societally and biologically relevant, most research only reports sex assigned at birth. Thus, there is an argument for considering gender identity in data analysis, or even for instead investigating the effect of sex- and gender-related factors on medical outcomes, suchashormonelevelsandgenderstereotypes.
Ultimately, most justifications for excluding females from studies have been rebutted, and there is a growing understanding that diversifying research, to include not just cis women but also individuals of transgender and non-binary gender, along with people of non-white ethnicities, will improve our understandingofdisease,drugsafety,andbiologyas awhole
HECK TH C
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