{react} Issue 12

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Science by Newcastle Students Latest science news â–Ş The limits of medical trials 3D electron microscopy â–Ş The bumblebee sweet tooth

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e are surrounded by matter and creatures that can’t last forever; their life expectancies are predefined. Above all other limits, this limit looms first and foremost. Yet, as we make discoveries that demarcate the boundaries of our universe ever more clearly, we should not despair.

Knowing one’s limits can prove very useful: as individuals, when moderating intake of alcohol and other substances; as planetary stewards, in protecting Earth by understanding its tolerances; and, as an inquisitive species seeking objectivity, in establishing programmes of scientific and clinical research that address pressing gaps in our knowledge.

In terms of knowledge, we are privileged. More than any other that has come before it, our generation is best positioned to understand, and thus solve, some of the greatest problems facing humanity. But we must not ignore the limits of our understanding. Being aware of the limits of drug therapy allows for better outcome prediction. An appreciation of translational limitations of animal models, or technological limitations of microscopy, can help us apply these approaches most appropriately, guide improvements to existing solutions, and direct searches for future alternatives. It is this awareness that drives evolution and progress.

In this issue, “Limits”, we have tried to gather articles that sit at the expanding horizon of current research and scientific news. We hope you find the submissions sufficiently entertaining, informative and inspiring that perhaps you will yourself consider submitting to a future issue of {react} and following us to the cutting edge.

RC & EK, 2019

MEET THE TEAM EDITORS: Emma Kampouraki and Ryan Calmus LAYOUT AND DESIGN: Adam Azzi, Ryan Calmus, Alethea Mountford NEWS EDITOR: Elizaveta Olkhova SUB-EDITORS : Cassie Bakshani, Ryan Calmus, Joanna Ciafone, Julia Concetti, Christina Julius, Emma

Want to edit, organise or design this magazine? Get in touch!

Kampouraki, Jess Leighton, Alethea Mountford, Laura Sabater BLOG MANAGER: Joanna Ciafone BLOG TEAM: Cassie Bakshani, Chris Cole, Georgia Collins, Annie Derry, William Gan, Emma Kampouraki,

react.mag.team@gmail.com

Elizaveta Olkhova, Leonie Schittenhelm, Joseph Smith PUBLIC RELATIONS : Justin Byrne and

@react_magazine

facebook.com/react.mag

Emma Kampouraki

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Contents News 4 What’s new in science?

Limits of alcohol consumption 8 Your body’s perspective

Senolytic therapy 10 Its promises and limitations

News What’s new in science?

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Clinical research & the elderly 12 The challenges of helping the ageing population

Current cancer models 14

Is effective drug discovery being limited?

Success of medical trials 16 The long process of drug development

Interview with Dr Brook Galna 18 And his research on walking behaviours

3D Electron microscopy

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Beyond the limits of two dimensions

Limits of scientific research

Alcohol Your body’s response

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25

Looking into the anti-vaxx movement

Life expectancy lottery

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Links between social class and life expectancy

Bumblebee gustation

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Looking at a bumblebee’s sense of taste

Ageing of the common fruit fly 32 From household pests to superheroes

Red alert for our blue planet 34 The groundbreaking IPCC report

Book review 36 “Origin” by Dan Brown

Fruit flies The perfect test subject

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Fun and games 38 Take a break and enjoy a puzzle

NEWS

News

The latest science scoops from Newcastle Elizaveta Olkhova

Geordie anti-cancer drug Rucaparib (commercial name – Rubraca) approval in the EU and USA is a tremendous achievement of 30 years of research, led by Newcastle University scientists. The drug entered the first phase of clinical trials over fifteen years ago and the first patient’s prescription was made by Professor Ruth Plummer, who is a Professor of Experimental Cancer Medicine at the Northern Institute for Cancer Research, Newcastle University. This drug is the first one of its class of PARP inhibitors to be licensed in Europe for women with ovarian cancer who have a mutant BRCA gene. A mutation in this gene depletes the cells from one of the main types of repair mechanisms that serve to fix errors in DNA that occur naturally in cells, for example, during DNA replication that is required for the cell to undergo mitosis. Rucaparib acts

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by blocking yet another type of DNA damage repair mechanism, leading to a rapid buildup of high levels of mutated DNA in susceptible, continuously dividing cancerous cells. This level of mutation load triggers programmed cell death and tumour cells eventually die.

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Acipimox for treatment of mitochondrial disease Mitochondrial disease is a group of metabolic disorders in which mitochondrial function is compromised and energy metabolism and supply are reduced, affecting metabolically active tissues.

Patients present with a wide spectrum of symptoms ranging from exercise intolerance and problems with eye movement control to myopathy, epilepsy, liver disease and heart failure. In 2017, blogs.ncl.ac.uk/react

Medical Research Council has awarded the Wellcome Centre for Mitochondrial Research at Newcastle University £1.6 million to initiate a clinical trial to investigate whether a drug called Acipimox can improve mitochondrial function in patients with myopathy caused by mitochondrial dysfunction, led by Dr Gráinne Gorman. This drug is already licensed for patients with high cholesterol levels to prevent diabetes and cardiac diseases, however it has been previously shown to increase generation of ATP – the molecule which is produced during energy metabolism in mitochondria – and hence may improve the energy supply to the muscles and alleviate muscle weakness.

This trial is due to begin in spring 2019 with great hope for promising results due to vital need for effective pharmacological intervention to be delivered to patients.

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PHOTO: NEWCASTLE UNIVERSITY

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NEWS related health complications. However, maintaining patient compliance on such a radical diet might be challenging. v

Anticholinergic medication may lead to dementia later in life Diet to reverse diabetes type II Calorie restriction diets have been trialled

by Newcastle University researchers back in 2016 in patients with newly diagnosed diabetes type II, which can be triggered by risk factors such as obesity. They have found a lowering of blood glucose following a strict low-calorie intake diet in 12 out of 30 patients recruited, in whom diabetes type II was remitted. This study has provoked NHS to take on this strategy to reduce the costs of diabetes treatment as part of the NHS long term plan. At the initial stages, up to 5,000 patients with diabetes will be recruited and will be given a liquid diet of approximately 800 calories a day (compared to approximately 2,000 or more calories recommended daily intake) for the period of three months to check the effects of such low-calorie diet on diabetes.

This diet would help to battle obesity by promoting weight loss in patients and hence it would help with insulin resistance in type II diabetes and other obesity-

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The largest study to date on the effects on anticholinergic treatment effects on dementia has been conducted at Newcastle University and led by Dr George Savva. Some antidepressants, Parkinson’s and bladder medicines are known to decrease the amount of acetylcholine – one of the main neurotransmitters in the nervous system – hence are known as anticholinergic medication. The study has analysed many thousands of prescriptions given to people with and without dementia and has found a strong link between using an anticholinergic drug for a long period of time and development of dementia later in life. In dementia, there is a general decrease in the level of acetylcholine produced in the brain, hence anticholinergic drugs may contribute to the decline of this transmitter. This study highlights the importance of careful selection of prescribed drugs in aged population in whom polypharmacy is common.

Find out more about these stories and more on the Newcastle University website at www.ncl.ac.uk/press/news blogs.ncl.ac.uk/react

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IN FOCUS

The limits of alcohol consumption: your body’s perspective Ben Slater F. Scott Fitzgerald, the acclaimed author of ‘The Great Gatsby’ once said, “Here’s to alcohol, the rose-coloured glasses of life.” Alcohol is so often seen and talked about that we forget it is a drug. Although not an illegal one, alcohol can be a severely harmful drug if it is abused. But where exactly does our body draw the boundary between recreation and discretion when it comes to alcohol?

Alcohol – a backstory Scientifically, the substance we most commonly term ‘alcohol’ actually refers to ‘ethanol’, which is produced by the natural fermentation of sugar. It is believed humans have been producing alcoholic beverages for thousands of years with the earliest date during the Neolithic era, the latter end of the Stone Age around 12,000 years ago. For many years, particularly during the middles ages, alcoholic drinks were a more hygienic alternative to water (that was often contaminated with sewage and other dangerous bacteria). Nowadays, however, alcohol is primarily drunk socially and the concentration of ethanol it contains is a lot higher. The amount of ethanol within a drink is known as the alcohol by volume (ABV, given in vol%, or tenth of a percent) value. Drinks with a high ABV are likely to cause you to become intoxicated faster as you are consuming more ethanol in a shorter period of time.

Dealing with alcohol – your body’s coping strategy When you consume alcohol, the ethanol it contains is absorbed throughout your

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gastrointestinal tract (stomach and intestines).

Your stomach is where ethanol is absorbed the slowest and it is because of this many people suggest eating before drinking as the alcohol consumed alongside or after eating spends longer in your stomach so is absorbed at a slower rate. After absorption, the ethanol passes to your liver where the majority of it is broken down before it enters the general bloodstream.

It has been shown that the speed at which people absorb, distribute, and break down ethanol varies as much as three to four times between individuals. It is thought that women generally have a lower tolerance of alcohol than men due to having a lower body water percentage (on average, it is 52% for women and 61% for men). Despite two people of different sexes weighing the same, typically a man will dilute the alcohol in his bloodstream more and lower his blood alcohol content (BAC) to a value below that of the woman.

The rate at which the body can break down alcohol is set by your physiological parameters and availability of specialised enzymes. The

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main enzymes responsible for this process are a group collectively known as alcohol dehydrogenases (ADs). Present predominantly in the liver but also found along the gastrointestinal tract, ADs take an individual molecule of ethanol and break it apart to produce acetaldehyde (a substance thought to be highly carcinogenic and the reason you feel terrible during a hangover). The acetaldehyde is then converted by aldehyde dehydrogenase (another enzyme) into acetate which can then be broken down into carbon dioxide and water for excretion out of the body.

vol%. Ethanol has now started to affect your forebrain (the area most commonly associated with emotion) resulting in aggression/ depression alongside inappropriate social behaviour as the neurons that normal prevent you from acting wildly are now no longer functioning properly. You may also notice visual tracking and coordination are impaired as ethanol begins to subdue the neurons in your cerebellum - located at the back of your brain at the base, your cerebellum is responsible for your fine motor skills.

The invasion of alcohol into the brain Ethanol causes most of its noticeable effects after crossing the blood brain barrier. The resultant effects, often perceived as pleasant, are in fact due to a proceeding intoxication which can severely damage your brain cells, or neurons. Crudely speaking there are two types of neurons: excitatory and inhibitory. As their names suggest, excitatory neurons are responsible for increasing the activity of other neurons whereas inhibitory neurons act in opposition. Ethanol is thought to enhance the action of inhibitory neurons whilst suppressing the activity of excitatory neurons. This leads to an overall depression in brain activity and produces the qualities often associated with being drunk. Different levels of “drunk� result from spreading sedation throughout the different brain areas: A night out according to your brain After one to three drinks your BAC is around 0.06 vol%. and the sensations of relaxation and numbness begin to set in. Ethanol has intercepted the neurons in your cerebral cortex; suppressing your awareness and judgement of the outside world. Most people want to stay at this level of intoxication and so mistakenly drink more in an attempt to maintain the pleasant feeling.

Four to six drinks later your BAC is around 0.20 blogs.ncl.ac.uk/react

Eight drinks plus and the brain is nearly swimming in ethanol with your BAC approximately 0.41vol%. By this point, the majority of your brain areas are affected by ethanol and you begin to slur your speech and lose balance altogether; potentially becoming unconscious. If alcohol consumption exceeds this point, with a BAC of 0.50 vol% then death is possible as the body goes into a deepened state of sedation and acute hypothermia as control over temperature regulation and breathing is lost.

As dangerous as it is, alcohol is used by the majority of the population of the world on a regular basis. The limits of alcohol seem to remain a blur for many as we consume large quantities to enjoy its strange and intoxicating upshot. Every time we drink, our bodies fight to keep the presence of alcohol from being overwhelming; constantly trying to balance the limit between enjoyable intoxication and unconscious oblivion. At what point will we say we’ve had enough?

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RESEARCH

The promises and limits of

senolytic therapy Hanna Salmonowicz

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s a PhD student working on molecular bases of ageing, my daily task is to maintain a culture of cells. I let my cells get comfortable in a plastic dish with a good amount of nutritious media, wait for them to divide, and when the dish becomes overcrowded I split them. What is striking even with years of experience is that I cannot maintain the culture infinitely. There is a limit to the number of divisions cells can undergo.

After about two months of culture, they enter a twilight state called cellular senescence when they are still active but irreversibly stop dividing. Cellular senescence is also activated as a response to runaway divisions of cells on the verge of tumour transformation, or to harmful x-irradiation or chemicals. Internal signals harness the stressed cells tp produce a cocktail of proinflammatory molecules in force to influence the behaviour of neighbouring cells and immune cells. Senescence evolved as an anti-tumour mechanism and prevents the multiplication of damaged or dysfunctional cells. If my senescent cells were not in a dish, but still a part of a tissue, they would eventually become eradicated by the guards of the immune system.

Even a glimpse through a microscope allows me to see massive changes to senescence cell’s shape and size. Cells become huge, take on irregular shapes, and become filled with a great

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many nasty granules. More detailed analysis shows that senescent cells accumulate various forms of damaged macromolecules, fat, and even blobs of their own DNA that has drifted from the nucleus. Mitochondria, the cellular powerplants left over from the cells’ ancient bacterial symbionts, form a neat and elegant network in the young and healthy fibroblasts.

In senescent cells, they becomes a dense forest of innumerable trunks and branches; moreover, mitochondrial DNA – their own little steering centres – multiply, and some even leak out from the mitochondria to the cytoplasm.

The process of young cells becoming senescent could be compared to a slim and pretty ballet dancer becoming a monstrous and abominable Jabba.

All these fascinating changes happen in my dish within a single week. However, do we also find such cells in human bodies? Features that are characteristic to senescent cells are in fact being found across multiple organs.

Importantly, the number of senescent cells rise notably in several conditions, such as obesity; in patients undergoing chemotherapy or radiotherapy; and finally, across diverse organs as we grow older. Their number is linked to age -related pathologies and frailty of elderly patients. These observations made researchers wonder whether accumulation of such dysfunctional, proinflammatory "zombies" across multiple types of tissue can be a causal factor for age-related diseases. To check what role senescent cells play in the ageing process, they developed a senolytic strategy that would specifically target and eliminate senescent

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cells. The first step is to identify a weak spot of senescence cells. Their “zombie-like” nature has been found to be one of them. Senescent cells, while being damaged and dysfunctional, must utilise strong “anti-death” signals to remain alive – signals which are not active in the majority of healthy cells. When drugs target the machineries responsible for their survival, senescent cells die.

Finding a way to make senescent cells commit suicide led to a blossoming of the senescence field: numerous publications appeared showing the beneficial effects of eliminating senescent cells in age-related conditions as diverse as atherosclerosis, liver steatosis, osteoporosis, Parkinson’s and Alzheimer’s disease. Mice who underwent the treatment in their middle age, or even when they had reached their autumn years, turned out to live disease-free for longer, with improved kidney, heart and fat function and, importantly, higher levels of physical activity.

The potential of a senolytic therapy is immense.

One of the biggest challenges of medical care for elderly patients is the problem of multimorbidity: most people who reach the age of 65 suffer from more than one chronic disease. As the newest discoveries show, the basis for many of the disease as seemingly unrelated as osteoarthritis and diabetes do have a common denominator: cellular senescence. Laboratories and companies are now working to bring senolytic therapies to life, and are doing so with the motto of bringing about healthy ageing.

However, as is the case with every therapy, senolytic therapy has its limits and may have side-effects. The first clinical trials of senolytic treatments are only just beginning. Despite this, they are already being advertised in massmedia as the ultimate anti-ageing treatment, with evidence taken in particular from research using mice as model organisms. Do humans respond as well as rodents to senolytic blogs.ncl.ac.uk/react

treatments?

One of the main concerns with the senolytic approach is the potential and as yet unknown effect on healthy cells. This challenge resembles the major trouble with cancer therapies that are designed to remove only the tumour cells, yet in fact affect the whole body. There are some indications that certain pharmacological compounds acting as strong senolytics may actually disturb the healthy cells and make them go down the senescent path!

Another complication is linked to an additional role senescent cells play in healthy organisms.

Namely, transient senescent cells have been spotted at wounds where, thanks to their proinflammatory mode, they facilitate the healing process. Senescent cells are also involved in the prevention of tissue fibrosis in the liver and kidneys. Recent literature suggests not all senescent cells may be so bad. Ideally, only the long-lived senescent cells that evade clearance by the immune system should be got rid of.

Both the above-mentioned concerns regarding senolytic therapy indicate that “one-shot” rather than chronic therapies would be advised.

The final question is whether senolytic therapies are actually anti-ageing. The most fundamental cause of ageing is the molecular damage to cellular and extracellular components that takes place in all tissues of our bodies. Whilst all cells accumulate damage during ageing, only some cells enter senescence. Senescence is a response to an overload of damage and stress. After a senolytic treatment, and possible amelioration of agerelated diseases, more cells would inevitably become senescent with time; and subsequent treatment could exhaust the regenerative potential of the remaining cells. Therefore, this strategy seems to buy us more time to continue studying yet more astonishing phenomena, and to look for new treatments, rather than to grant immortality. The near future will show the length and quality of the time we may have left.

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FEATURE

Crossing the boundaries: challenges of clinical research involving the elderly Emma Kampouraki

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n 2017, global population consisted of 12.5% people aged 60 or over, with 8.7% aged 65 or over, according to the United Nations. In the UK, the population is growing even older, with 18.2% being 65 or over and 2.3% over 85. In this fast-ageing population, there is a pressing need to find the best ways to deal with medical conditions that are mostly prevalent in the elderly (defined as over 65 years by the WHO), but this task can only be described as complicated.

It is estimated that 85% of older adults have at least one chronic health condition and 60% have at least two chronic conditions. Diabetes, cardiovascular disease, arthritis, dementia, falls, osteoporosis and cancer are just some longterm conditions of a lengthy list prominently affecting this demographic. Hence, an older person suffering from multiple conditions is the rule rather than the exception. However, due to the targeted development of the UK’s

After all, we all age sooner or later. healthcare system, the elderly population is mostly well taken care of. As set out in the NHS Operational Planning and Contracting Guidance 2017-19, the NHS works hard to ensure that everyone can access services on an equal footing.

It is undeniable that widening access to hospitals and general practitioners often means widening access to clinical research facilities

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too. Clinical research is responsible for determining the safety – as a first priority – and the effectiveness of all kinds of treatments, including medications, non-pharmacological interventions, diagnostics and medical devices.

Without clinical studies in a drug’s target population, in this case the elderly, it is impossible to be certain about the drug’s safety and efficacy in practice. Certain physiological and practical factors affecting older individuals make targeted clinical research especially important in this case.

Adverse drug effects can occur in anybody, but some characteristics of older patients make them more susceptible. Age-related changes occur in the way drugs are absorbed, distributed, metabolised and excreted, and in how they act on the human body. If we compare groups of patients separated solely on the basis of age, we tend to see an increasing proportion of patients exhibiting extreme body mass within the older demographics.

Historically, it was uncommon for the elderly to be obese. However, The 41st edition of Social Trends, published by the Office for National Statistics, shows that in 2008-09, the prevalence of obesity in the groups 65-74 and over 75 years was very high; 81% of males and 74% of females between 65 and 74 years, while 71% and 61% respectively in the group over 75 were overweight. These figures are in line with observations that total body fat increases with age, reaching a peak at about 70 years of age.

On the other hand, studies have previously associated weight loss with mortality risk in the very old. Those who are frail, malnourished and are suffering from long-term conditions such as cancer, mostly have lower body weight and blogs.ncl.ac.uk/react

reduced appetite. This affects absorption of drugs as well as storage of nutrients in the body (e.g. fat-soluble vitamins).

Similarly, renal and liver function are more or less compromised with increasing age and depending on other comorbidities. Many older people do not excrete drugs in urine at the same rate as a younger adult due to age-related renal impairment. This requires adjustment to a lower dose to ensure that the drug does not accumulate in an older patient’s body due to reduced elimination, and that drug levels in the blood therefore remain safe. While the kidneys ensure blood is filtered, the liver plays a central role in the detoxification of the body by metabolising substances including prescribed drugs. The majority of drugs can be toxic unless metabolised – and a few others won’t act at all unless metabolised. Changes in liver function with age include decline in liver volume, reduced metabolic enzyme production, reduced regenerative capacity and increased susceptibility to liver disease.

Polypharmacy refers to the concurrent use of multiple medications by one person and is a major concern among healthcare professionals.

Among the elderly, 90% take at least 1 drug per week and 12% take 10 or more drugs per week.

Women typically take more drugs than men.

Older people who are frail, hospitalized or in a nursing home take the most drugs. Nursing home residents are prescribed an average of 7 to 8 different drugs to take on a regular basis.

Older people also take many over-the-counter drugs, which are potentially hazardous due to interactions with their treatments and increased exposure (in the latter case, the prescribed drug can remain in and act on the body longer than intended).

It is not easy to involve the elderly in clinical research. Geriatricians are understandably reluctant when they assess the risk to their patients to be greater than the benefit. An example is that of the patient who, whilst taking a drug that might cause bleeding, is asked to participate in an interventional study but lives at a significant distance from an accident and emergency department. The potential adverse event of uncontrolled bleeding might be fatal if the patient doesn’t receive immediate care. Notwithstanding, in many cases, older people happily agree to participate in a clinical trial, provided they understand what it involves. To increase participation, study design is crucial, as an observational study will attract more volunteers than a study that requires the volunteer to make significant changes to their daily routine.

Further attention must be given to the issue of widened participation by the elderly in clinical research, taking into account the diverse physiological changes our bodies undergo during the process of ageing. New medication and interventions need to be well examined in the target population before they are approved to enter the market. Due to the multiple above mentioned age-related changes our bodies eventually undergo, the pharmacological activity of drugs may alter in complex ways.

Older patients are more likely to occupy diverse categories when it comes to treatment efficacy, dose requirements and lifestyle changes.

However, enabling older people to participate in carefully designed clinical research programmes will lead to a better understanding of these crucial age-related factors and to improved future healthcare for our ageing population. After all, we all age sooner or later.

Parasitoid wasps are parasites that are also parasitised themselves blogs.ncl.ac.uk/react

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FEATURE

Are current cancer models limiting effective drug discovery?

Joseph Smith

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ancer is defined as an uncontrolled division of abnormal cells, resulting in a malignant growth or tumour. Recent reports suggest that approximately half of us will be diagnosed with the disease in our lifetime. Moreover, it is predicted that cancer incidence rates will increase by 68% from 2012 to 2030 worldwide.

Fortunately, our understanding of how cancer occurs and progresses is also increasing, inherently providing opportunities to identify novel druggable targets. However, our improved understanding has also revealed unforeseen challenges that complicate the journey of new drugs from bench to bedside.

This is evidenced by the fact that a staggering 95% of lead drug candidates do not make it to the clinic. But why? One of the main reasons is our inability to accurately replicate cancers as they occur in humans. Researchers currently employ a wide array of cancer models in order to understand the biological processes that drive cancer and to test potential therapies. In this article I will discuss some of the most commonly used cancer models and how they might be limiting effective drug discovery.

The power (and drawbacks) of immortality The first and probably most well-known cell line was established in 1951 and derived from a cervical adenocarcinoma tissue biopsy.

Henrietta Lacks, the patient from whom the biopsy was taken, succumbed to her cancer only months later however HeLa cells are still used in cancer research to this day. HeLa cells,

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like other immortalised cell lines, have the ability to grow and divide indefinitely.

Furthermore, researchers can easily manipulate cell lines, for example, by increasing or decreasing the amount of a particular protein.

These traits have resulted in their routine use and they are an essential tool for cancer research, allowing scientists to elucidate the molecular biology of cancer cells. However, cell lines represent a massively simplified version of human cancers, lacking heterogeneity and a tumour microenvironment, including an immune system. These differences mean that a drug that is effective in vitro will not necessarily perform as well when applied in vivo.

Of mice and men In order to better recapitulate human cancers scientists will often utilise mouse tumour models, establishing cell linederived xenografts within immunocompromised mice. After the cancer cells have been implanted researchers may then treat the mice with a novel anticancer drug, with the view of slowing or ideally preventing cancer growth. Mouse models allow for

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evaluation of new therapies in vivo, within an environment more similar to that seen in humans. For example, the cancer cells have the ability to interact with the microenvironment in which they’re placed. Though, by using cell linederived xenografts these tumours still lack the inter-tumoural heterogeneity seen in the clinic.

Notably, this heterogeneity is likely one of the reasons for low response rates seen in many clinical trials, as small populations of drugresistant cancer cells can ultimately repopulate patients’ cancers. Genetically modified mice models of cancer also represent powerful tools, whereby oncogene overexpression mirrors human disease, such as the MYC overexpression-induced cancer model.

What are the alternatives?

Both cell lines and mouse models are useful however both have major limitations and do not capture the complexity of human cancer; as a result, novel anticancer drugs that prove to be effective in these models often do not have the same effects in humans. So how do we solve this problem? With advances in technology scientists have developed a multitude of techniques that aim to overcome the aforementioned issues and are coming ever closer to creating an environment that accurately reflects human cancers.

patient-derived xenografts which, unlike cell line-derived xenografts, retain the intertumoural heterogeneity seen in patients.

Instead of implanting cancer cells cultured in the laboratory researchers use cancerous material from a patient biopsy, forming tumours in vivo. Notably, patient-derived xenografts are identical to the primary tumour from which they originate in a number of ways, including gene expression. This is an incredibly useful trait which researchers have been able to exploit to the benefit of the patient.

Specifically, if a patients’ cancer harbours a particular mutation that renders it more reliant on a certain protein or pathway clinicians may choose to administer drugs that inhibit said protein or pathway, possibly killing the cancer cells. On the other hand, this method is timeconsuming, making it less useful when such decisions need to be made quickly, which is often the case. The nature of the technique also makes it less amenable to high-throughput screening, limiting its impact in terms of progressing new drugs through to the clinic. A second example is explant culture, wherein surgical specimens are grown in culture in the laboratory. This model also retains many of the same properties as the primary tumour while facilitating medium- to high-throughput drug screening. However, researchers are faced with many of the same issues as with previous models, such as the absence of a tumour microenvironment and immune system.

Despite this, our knowledge and understanding of cancer continues to grow and new models are continuing to emerge. Recent research has shown that it is possible to combine a number of techniques including explant culture to mimic the tumour microenvironment and immune interactions present in humans. Still, a balance must be struck between how closely a cancer model correlates with the clinical setting and how easily the technique can be used to test the efficacy of new anticancer drugs.

One such example is blogs.ncl.ac.uk/react

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FEATURE

Limiting success: why medical trials are doomed to fail Jess Leighton

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ew drugs are estimated to require over $1 billion investment to get them to market, meaning drug companies are keen to market and reimburse themselves. However, racing to a positive result isn’t the best thing for patients.

Drugs can be approved for use on large populations on the basis of trials on very small, select groups, which leaves the marginalised groups at massive risk.

From initial creation of potential chemicals, to testing on tissues, animals and finally humans, the process of drug development is long and complex. Clearly, the price of failure in pharmaceutical development is high, and consequently medical trials are designed to maximise the likelihood of significant results which will get their drugs approved and on the market. For this reason, investigators want to ensure that any effects in the trial are due to the drug, and nothing else. To this end, people with other diseases, on other drugs, and the very old and very young are often excluded from trials. However, a lot of drugs are taken by older people, who are particularly more likely to take other medications (one study found that over 17% of over 65s are on 10 or more drugs). So their exclusion from trials may make a ‘successful’ result more likely, but is that really any benefit if it doesn’t apply to the people who need it?

There are many complicating factors in pharmaceuticals. Patients are well aware that drugs affect different people in different ways-

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some drugs, like warfarin, need to be carefully monitored person by person. Some drugs, like thalidomide, are known to have different effects in pregnancy (thalidomide was famously prescribed in the 1950s and 60s for morning sickness, causing serious birth defects). Some drugs, like tamoxifen, will only work if your cancer cells have a particular receptor. In the fine print though, we find pharmacogenetics (the study of how your DNA will affect how well drugs work for you) and environmental factors (amiodarone, a drug to treat abnormal heart rhythms, can cause sensitisation to sunlight).

While these risks may be small, they can also be very severe, so shouldn’t be brushed under the carpet.

The solution is by no means obvious or simple.

Since the thalidomide scandal, very few drugs are licensed in pregnancy due to the lack of trials involving pregnant women. Many medications are prescribed and taken in pregnancy, but at the risk of the prescriber and the mother. Similarly with children, many medications are dispensed ‘off-label’, or for a different reason than the licensed use (usually for adults only). This caution is not extended, however, to patients with a different genetic profile, from a different ethnicity or of a much older age group than those involved in the trial. blogs.ncl.ac.uk/react

So both patients and prescribers are going out on a limb by using them, with potentially disastrous consequences.

The solution is by no means obvious or simple.

One technique is Phase 4 monitoring or the socalled ‘yellow card’ scheme, where newly licensed drugs are highlighted to prescribers so they can report side effects or problems. But this is done once a drug is licensed and available to use, so thousands of people may already be taking it. Schemes to improve drug safety can be successful- for example additional

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analysis to look for trends in specific groups, or encouraging patient and prescriber education.

The safety information included with drugs is often a hefty and intimidating legal document, but could be a great place to add postmarketing findings like side effects.

There is no quick fix when it comes to drugs, and the limits of our current approach to medical trials are something that the public need to be aware of, prescribers need to be mindful of, and drug companies need to tackle head on.

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PROFILE

Interview with

Brook Galna Cassie Bakshani & Ryan Calmus Dr. Brook Galna is director of the Sport and Exercise Science programme at Newcastle University, and a member of Newcastle’s Brain and Movement Research Team. He spoke to us about his career, and the relationship between movement and neurodegenerative disorders.

What have you been doing this week?

I’ve been meeting with second-year students about their research proposals in preparation for their third-year projects. Many of our students have deep personal connections to sport, so we’re encouraging them to come up with their own research ideas, thinking about the challenges they’re interested in. As the next generation, I think they have real potential to change the community they’re in, both locally, and then through asking bigger questions, through business initiatives, through public institutions or research, I think they can have a real global impact as well.

How did you end up on this career path?

My career pathway wasn’t straightforward and I ended up doing two degrees. In my Bachelor of Arts degree I majored in Philosophy and the History of Ideas, and Psychology. In my Bachelor of Applied Science, I majored in Exercise Science and Exercise Behaviour and took a minor in Health Promotion.

I’ve always loved being outdoors, but I was also interested in how we evolved, how we develop from birth into very cognisant adults, and how we can prevent things breaking down, both due to an acute occurrence or natural ageing, and

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help individuals to adapt and compensate in a pragmatic way. I did most of this thinking at Deakin University in Melbourne, and then at the University of Victoria in British Columbia. I was then offered a fantastic position back in Australia, so I returned for a year-long paid postgrad internship at the Australian Institute of Sport. There I worked in the biomechanics department, with the track and field and winter sports teams.

I then went back to Deakin University, where I researched motor control dynamics of human behaviour. I was interested in how we control our limbs and the associated energetic and cognitive costs. I was very fortunate as I had a fantastic supervisor, Tony Sparrow, who was instrumental in my approach. We’d have informal chats and he would say things like “why do you think that flock of birds overhead are flying in that formation?” leading me to think about energy efficiency and coordination.

In doing so, he gave me the freedom to come up with my own project.

Tell us a little bit about your current research.

My research is now based around neurodegenerative disorders and understanding the interplay between the brain and behaviour. My focus is on biomechanics,

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Dr Brook Galna stands in front of a screen showing a scene from a Kinect-based exercise game designed for, and tested by, people with Parkinson’s Disease, the ‘PD-Kinection’ project which is the physics of how people move.

We’re a multidisciplinary team working with age-related disease, like Parkinson’s disease and dementia. By looking at the way we move and how we walk, we’re trying to find ways of detecting signs of incipient disease before it could otherwise be detected, in a relatively simple and non-invasive way. At least two thirds of people with Parkinson’s fall over every year and a lot of these will happen when they’re walking, so we were gathering evidence to suggest why this happens.

that it is so complex, if you make a slight change because, for example, you have a new pair of shoes that give you a blister, the way you walk will change slightly. If you have a subtle lesion in the brain, it’s the same thing, because the brain is so important in defining how we walk, and we can measure these changes. By measuring a very complicated task that subtly differs over time in response to disease, we can learn more about that disease: whether it is present or not, how progressed it is, or how it responds to treatment.

Why is walking an important marker of cognitive decline in conditions like Parkinson’s?

How do you measure these kinds of changes?

When walking, you’re effectively trying to balance your body mass one metre above the ground on a constantly shifting and unpredictable surface. The way we walk also changes throughout puberty and we don’t achieve consistency until age 18-21, when our adult gait and walking patterns solidify. Given

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There are many ways, from very simple techniques such as observational measurements, to very technical, quantitative measurements. We simplify these methods so that they can be adopted into clinical practice or a community setting.

To measure how fast someone walks over a given distance, we only need a stopwatch and

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PROFILE simple mathematics. But walking isn’t just as simple as how fast you walk, it’s very sensitive to changes, and there are many reasons why you might start slowing down – that’s why we also integrate more complex techniques. If we video someone walking in the clinic, the observer can examine how someone’s knees bend, if they bend, or whether they are listing to one side due to a compensation. Clinicians can look for clusters of symptoms that experience suggests are indicative of certain problems. Filming and then slowing this down is also a fantastic feedback tool, allowing patients to see how they move and learn from it – because often these things change so slowly over time, we don’t recognise these changes in ourselves. These simple tools are ubiquitous.

We get this really amazing picture of how somebody is moving Beyond simple video, there are other techniques such as stereophotogrammetry – basically, 3D motion capture. As in the making of "Lord of the Rings" or "Avatar", where people used this technique, you place reflective markers on the body and, by recording with multiple calibrated cameras, you can triangulate the position of each marker and actually determine changes in the angles of joints whilst people are walking. These advances have been instrumental in allowing clinical gait analysis to be used as a tool to help clinicians and consultants make really important decisions about, for example, surgery in people with cerebral palsy. In conjunction with the physiotherapy workup, clinicians will look at the way these patients move and with this technology they'll be able to isolate what muscles are active when, and then they can consider how that's affecting this

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person's walking. If you don't have that information, you may be making the wrong surgical decision. For example, if you think it's the calf muscles which are spastic, and you lengthen these at the Achilles tendon, you may improve function if these are truly spastic muscles – but if you're wrong and the problem is actually up in the hamstrings, then you've actually made things worse for the person and they may no longer even be able to walk.

Stereophotogrammetry has been a huge advance here, as we need the best evidence we can get.

We need to marry in other systems, too. By measuring the electrical activity of the muscles while people walk, and considering this in conjunction with how they're moving – the kinematics, the patterns of their joint movements – we obtain more information about muscle activity and how that's affecting mechanics. That gives more information to the clinical team when they're deciding what surgical procedures need to be undertaken.

The other thing that helps are more direct measurements of force, which comes down to the crux of what biomechanics is, that is, how forces work both within and on the body to create or resist movement.

Marrying all of these techniques up, we get this really amazing picture of how somebody is moving.

How far away are we from being able to give a patient at risk a phone with an app on it and say "go away and we'll monitor you for a month using your phone’s built in accelerometer?"

Measuring gait in a controlled environment is a costly business. To be able to have a “lab-on-achip” is huge – and it is a growth industry, the use of these accelerometers, and inertial measurement units in general. In your phone, you have all of the tools you need to get a fairly good reflection of not just how fast you're moving, but whether you have a limp to one blogs.ncl.ac.uk/react

side or not, how variable you are.

Where are we at the moment? There are a number of studies running currently, which we're involved in here, both related to Parkinson’s and other disorders, and also to normal ageing, where we're asking people to go away and wear these tiny little sensors, not even the length of your thumb and only about twice as wide. You just stick it on your back, and leave it on for a week. These sensors get sent back and… this is where it's amazing working in a multidisciplinary team. I get to work with computer scientists, bioengineers, biomechanists, clinicians and nurses to interpret this and discuss the important factors that we need to work on. We can start answering research questions in a very sophisticated way, which can then be applied in the clinic.

What manipulations can you carry out in order to test the limits of people’s walking ability?

There are many different paradigms. We might get people to walk under different dual task effects – that is, we might get people to listen to a story and they have to recall that story whilst walking, or maybe count backwards in sevens from one hundred. We're targeting different parts of the brain by using these different cognitive tests.

But there are also physical ways you can look at this; you can push people to their limits, for example by asking them to walk as fast as they can, or walk over things, or turn around things.

And something as simple as turning around can elicit amazing motor deficiencies in people with Parkinson's. You have something in more advanced disease called “freezing of gait” where somebody might try to start walking but their feet won't move – an akinesia – or they'll be walking and they start taking smaller and smaller steps, and they festinate to the point where they feel like their feet are stuck to the floor. Things like trying to turn, or to go

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through a narrow passageway – things we don't usually think about – can elicit this freezing of gait. As you can imagine, that has a huge impact on quality of life, and falls risk, and health.

In the lab, we try and replicate the ways in which people are being challenged in their own environment, but this can be taken even further. Some labs will shunt people – participants will be walking on a treadmill and the treadmill will suddenly stop, or researchers will physically present a barrier, to elicit a trip.

Here, it's not just a case of "Are you likely to trip?" but "What happens if you do lose your balance? Do you have appropriate responses?”

Some people with Parkinson's won't put their hands out when they trip, which means if they do fall, it might be on the head, or on the shoulder, which is obviously potentially horrific.

So it's not just assessing adaptation when things are working well and patients are in a good environment, but what happens when things go wrong and patients can't adapt. Being able to measure people whilst simulating normal conditions, or whilst actually walking in the community, is very attractive from a clinical point of view. But it comes with its own challenges, because we're going suddenly from a highly manipulated, controlled environment where we can objectively report on and replay movement, to unobserved gait. Is somebody in their house? Are they in the community walking? How do you take those types of stimulus into account?

To read the full interview go to blogs.ncl.ac.uk/react/brookgalna If you’d like to learn more about Dr Galna’s work in the Brain and Movement Research Group at Newcastle, please visit the following website: https://research.ncl.ac.uk/bam/

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OPINION

Beyond the limits of 2D:

3D electron microscopy Ross Laws “What does a mitochondrion look like?”, asks the lecturer.

“A sausage?”, replies the student eager to demonstrate their knowledge.

“Correct!”, says the lecturer.

“Wrong.”, says the microscopist at the back…

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his is a crude humorous example but a nugget of truth is buried within. Biological structures often don’t look like they do in the textbook when viewed in 3D. Although 3D light microscopy exists, there is always a limit to the resolution of images due to the wavelength of light. Super-resolution microscopy can break passed the usual limit of light of microscopy. However, even though some super resolution systems can resolve separate objects in as small as about 20 nanometres, this is mostly on single points of fluorescence, rather than 3D blobs.

A transmission electron microscope (TEM) has a much higher resolution (and consequently magnification) but lacks the imaging depth of, say, a confocal microscope, which is a point scanning light microscope that can image deep into fluorescently stained tissue. This is because a TEM images an ultrathin section (slice) of tissue only 70 nanometres thick. To put that in perspective, a strand of spider silk is 0.003mm or 3000 nanometres thick. A TEM works like an old projector, with the beam of electrons passing through the section and projecting the image onto a camera or screen. So, a TEM image is essentially 2D. Building up a 3D TEM image requires a time-consuming technique

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called serial sectioning.

In the last two decades however, machines have been developed that can section a sample of tissue or cells inside an electron microscope.

One method of sectioning the sample is with a diamond knife. These systems automate the process of cutting and imaging a sample. So, the system cuts a section away and then images, over and over. This builds a stack of images slice by slice. The technique is called serial block face -scanning electron microscopy (SBF-SEM for short). Although it sounds complicated, the process is actually quite simple.

Imagine if an apple was sliced 1mm at a time and a photo was taken of the cut face of the apple. This would produce a library of crosssectional images of the apple. Now imagine you wanted to make a digital 3D model of the apple.

The first step to achieve this is a process called segmentation. Segmentation is where the object (the apple) is highlighted on every image.

This produces a cut-out, or segmentation, of the apple from every slice. These cut-outs can be assembled into a model, much like a laser cutter model. Now imagine doing the same process on a much smaller scale but for an animal or plant cell.

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Going back to the shape of objects in 3D, imagine you didn’t know what an apple pip looked like and someone showed you one of the apple cross sections we talked about earlier.

If the apple was cut horizontally, through the middle, you would see the pip and think it was a circle. So, you go and tell all your friends that apple pips are small and spherical in 3D. Then one of your friends cracks open an apple and shows you that they are actually teardrop or sometimes oval shaped.

This is pretty much the problem we had before high-resolution 3D microscopy. All we could see on a TEM was a slice of the cell. So, we could determine the basic shapes of organelles (structures inside the cell with different purposes), but some features were hidden.

Now, however, we can see the whole cell and the features of those organelles have been revealed - we now know the apple pip is an oval.

Mitochondria are one such organelle, often referred to as the power plant of the cell as they produce energy for the cell. Their role is actually much more complicated than the ‘power plant of the cell’ as they are involved in many other cellular processes. Mitochondria, across all tissue types, are an important area of

Far from always being oval or sphere, the nucleus can be multilobed, disk-like, or

shaped like a donut research at Newcastle University. A vast amount of research has been performed into mitochondrial genetics, and molecular structure and now that is being supplemented with higher resolution data about their shape and organisation in the cell. What researchers have found is they have a variety of weird and wonderful shapes across the different tissue types. For instance the 3D model compared to the traditional textbook view in the figures below.

3DEM has revealed that the nucleus of the cell also has some surprising features, just like it did with mitochondria. The nucleus is the control and data storage centre of the cell housing the DNA. Far from always being oval or sphere shaped, the nucleus of a cell can be multi-lobed,

Textbook mitochondria vs. a 3D model (scanned and segmented by Erin Cooks) blogs.ncl.ac.uk/react

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OPINION

The 3DEM system at Newcastle university is a Zeiss sigma VP SEM for imaging, coupled with a Gatan 3viewÂŽ for serial block face. Pictured being operated by the author Photo credit: Jeremy Domis. disk like or even have a hole in the middle like a donut. Some of these features are large enough to resolved on lower resolution 3D imaging systems but it is easy to verify that they are not artefacts in 3DEM.

An entirely new world of structural analysis has been opened by 3DEM The area that 3DEM is having the most profound effect on is connectomics. This is the field of study devoted to the mapping of networks and connections in the nervous systems of organisms. The neurons in the brain have tiny projections called dendrites. These are difficult to image on a light microscope as the gaps between them can be smaller than the

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wavelength of visible light. However, they can be imaged in 3DEM, which allows you to build 3D models of the smallest parts of the brains network of neurons. This allows researchers to construct neural network 3D models and then models in code then to use this to understand animal behaviour or create new algorithms.

An entirely new world of structural analysis has been opened by 3DEM and new techniques and microscopes are being developed. Some of these allow imaging of larger physical volumes, higher resolution imaging and faster data collection. However, 3DEM is producing more data than we can analyse. In the future, researchers in the field of 3DEM hope to speed up the process of data analysis to reveal more features hidden beyond the limits imposed by 2D microscopy.

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The limits of scientific research Christina Julius

The anti-vaxxer movement, Or what happens when trust in science is limited Vaccination is a medical success. Besides improved hygiene and nutrition – leading factors in infant survival – and relatively new treatments like antibiotics, immunisation contributes largely to our improved health. In the early 1900s every third child died before the age of five, but today early child death is a rare tragedy. Globally, 4.3% of children die before their 5th birthday; in developed countries this figure is around 1%.

Yet a paradox has emerged: the success of vaccines has harmed the credibility of the very concept of vaccination. It is incomprehensible to many parents that children must be injected with a “biological cocktail” in the absence of disease. Pseudoscience, conspiracy theories and scandal-driven media attention further hamper reasoning. Today, progress against serious infectious diseases is endangered by the anti-vaccination, or “anti-vaxxer” movement.

What is a vaccine?

A vaccine is a suspension of killed or attenuated (alive, lab-weakened) pathogens (harmful viruses or bacteria), which, when administered to an individual, elicits an immune response without posing the danger of a real infection.

The immune system is able to memorise pathogens it has encountered before, to be able to react to future encounters more rapidly and with greater strength. In principle,

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vaccination is like showing a mugshot of a criminal around before the criminal enters town, so they can be quickly reported and apprehended.

We have developed vaccines against many previously serious, common diseases such as smallpox, polio and, most recently, HPV (human papilloma virus, which can cause cervical cancer), allowing us to prevent both the infections and potential complications. Like other drugs, vaccines undergo a long process of drug approval, during which stringent safety requirements must be met (though in urgent cases, vaccines may be administered without clinical trials, when the risk of side effects is considered to be lower than that of disease).

Two outstanding vaccination success stories are the near-eradication of smallpox and rabies. Smallpox has a mortality rate of 30%, and those who survive often suffer disfigurement or blindness. Rabies has a fatality of practically 100% (with only 13 recoveries ever documented). These diseases can now be prevented by vaccination and are considered eradicated in the developed world (though wild bats can still carry rabies).

Realistic adverse effects of vaccines Opponents of vaccination argue that the risk of side effects outweighs the benefit of preventing disease. Indeed, recipients of vaccination can suffer from illness in rare cases.

In the worst-case scenario, allergies to components of the vaccine can lead to

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OPINION anaphylactic shock, and invasive infection of the live vaccine virus is possible in immunocompromised patients. Such patients should not be vaccinated, but can benefit from “herd immunity”. This is the concept that, if the vast majority of the population (in measles’ case, 95%) is immune due to vaccination or previous infection, it is very unlikely that the disease can spread to affect people who cannot be vaccinated. However, if a lower proportion of people are immune, there will be no herd immunity to protect unvaccinated individuals.

The history of the anti-vaccination movement: Do vaccines cause autism?

Arguably, the anti-vaccination movement is a symptom of a sociological condition: distrust in scientific evidence. Why do people lack faith in science? A look at the history of the anti-vaxxer movement makes this clearer.

In the 1950s a psychoanalyst, Leo Kanner, blamed the occurrence of autism on detached parenting (the so-called “refrigerator mother” theory), although he later retracted his theory.

At this point, the field of neurology was still in its infancy, and there were limited means of monitoring brain function. Meaning had to be found in superficial, simplistic explanations.

It was not until the 1980s that autism was redefined as a developmental neuropsychiatric disorder, and research began to determine

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potential causes. In 1998, physician Andrew Wakefield published a connection between the measles virus and autism. His research was inconsistent and irreproducible, and thus soon disproved, with his publication retracted in 2005. Nevertheless, and understandably, in a climate of self-blame, many affected parents embraced his “scientific explanation”.

Furthermore, it was easy to blame the measles, mumps and rubella live virus (MMR) vaccine because it was, as now, administered in early childhood, around the same time as the first signs of autism typically begin to show. Owing to the vaccine’s protection, measles would never emerge, but autism could of course still develop. The uninformed observer could easily, but falsely, conclude a negative cause and effect relationship was at work.

With measles on the road to eradication, and cases dropping, the increasingly administered MMR vaccine was instead blamed for the rising number of autism diagnoses. And the numbers are quite astonishing: in 1960 a groundbreaking study in England, surveying children 810 years old, reported 0.04% of the population was autistic; by 2000, this number had increased by a factor of 10. In 2011, a study in South Korea estimated a prevalence of 2.64%, meaning one in 38 children (aged 7-12) was autistic. What if, besides the attenuated measles virus, another component of the MMR

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vaccine was causing autism? What if this chemical was in other vaccines too? Today, voices blaming vaccines for autism are louder than ever, with anti-vaxxers refusing not only the MMR jab, but all vaccines. Nonetheless, the only reported connection between the MMR vaccine and autism remains Wakefield’s disproved theory.

The return of epidemics that could be eradicated by vaccination is not an inevitability Taking a step back The autism studies seemingly describe an alarming development. However, these results need to be consumed with scepticism. Wildly different criteria have been used to identify autism; while the 1960s study defined autism on the basis of underdeveloped language abilities and lack of responsiveness to others in an infant under 2.5 years of age, the Korean study included milder forms of autism such as Asperger’s syndrome, a diagnosis only applicable beyond later infancy. Generally, it is accepted that the prevalence of autism is around 1% of the population, but it remains unknown if this percentage is growing or stable over time. A single developmental cause of autism has still not been identified.

Results of the anti-vaxxer movement To scientists, the results of the anti-vaccination movement are tragically apparent. Reduced protection has predictably resulted in the return of numerous diseases. For example, in the UK in 1996, 112 cases of measles were documented. In 2018, between January and October, 913 cases were documented in the UK. Globally, death due to measles rose by 20%

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between 2016 and 2017, so that in 2017, 100,000 people died of measles – that is, 300 per day. Measles infection is, however, one of the more benign dangers of ceasing vaccination entirely, with a relatively low death rate and complications (30% of sufferers are admitted to hospital). Other preventable infections are more severe. For example, tetanus is a lifethreatening infection caused by soil-dwelling bacteria (Clostridium tetani, related to pathogen Clostridium anthracis, the producer of anthrax) contaminating the blood stream. As these bacteria proliferate in the body, they produce the tetanus neurotoxin. Untreated, the toxin causes progressively worsening muscle contractions, with death typically caused by suffocation resulting from permanently contracted respiratory muscles. Needless to say this is a painful and avoidable death that was common before the development of vaccines.

Take-home message There is a reason why humans live so far beyond their historic life expectancy of about 30 years: the remarkable progress of medicine.

Some negative consequences of modern medicine, such as antibiotic resistance, are problems we must face. But the return of epidemics that could be eradicated by vaccination is not an inevitability. Not vaccinating one’s child is highly irresponsible and a real threat to the child’s health.

Furthermore, parents who do not vaccinate their children endanger the lives of others that cannot be vaccinated, including newborns and the elderly. It is understandable that the scientific method, drug approval process, and vaccines’ mechanism of action may be unfamiliar to those without a scientific background. However, to some extent, we must all learn to rely on the expertise of others in cases such as this. Why? Because we must not let the limit of our own understanding be the reason for the regression of medicine.

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RESEARCH

The life expectancy LOTTERY Zoe Kirkham

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ife expectancy continues to rise across the UK, however disparities have widened illustrating marked inequalities in British society. These exist even within boroughs, such as Stockton on Tees. If you are born in Stockton town centre you can expect to live to 64, however if you live 4 miles away in Billingham west you can expect to live over 20 years longer. There appears to be a striking gradient between the north and south of the country, with life expectancy slowly decreasing the further north you travel. In the North East, it is still well below the national average. This may be explained in part by the high incidence of diabetes, stroke, heart disease, and obesity in this region. On top of this, the North East ranks amongst the highest in terms of drug and alcohol abuse. There is much evidence illustrating the correlation between deprivation and life expectancy, and it is prosperous areas that have seen the greatest gains.

You might wonder why such inequalities exist in a country that provides healthcare free at the point of use. The NHS most certainly improved the country’s health when it was first introduced in 1948 and continues to do so, but the healthcare sector’s impact on life expectancy has limits.

The social determinants of health The conditions in which people are born, grow up, live, work and age, each have their own impact on health and life expectancy. These are known as social determinants of health, and it

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is differences in these domains that are thought to be responsible for health inequalities. More specifically, these include early childcare and education, living environment, employment, working conditions and income. To tackle the widening disparity in life expectancy across the UK, social determinants of health need to be addressed.

Early life experiences Adverse experiences during early life have been linked to an increased risk of both physical and mental disease in adulthood, along with damaging health behaviours such as smoking and drinking. These have been shown not only to affect the current generation, but generations to come. Improving support for families by providing effective pregnancy care, financial support and accessible childcare can have a huge impact on the health of multiple generations, and help break the link between poor health and deprivation.

Employment The type of work carried out throughout one’s life can have a huge impact on health. There are obvious adverse effects to health of work in blogs.ncl.ac.uk/react

high-risk environments, however studies have also identified the presence of key psychosocial characteristics in certain work environments that have damaging effects on health. These jobs often prove demanding whilst giving employees little control and display an imbalance between effort and reward.

Additionally, low organisational justice, social isolation during work, job insecurity and shift work have all been associated with poor health.

With this in mind, we must find ways to prevent working environments such as these and implement strategies to promote human flourishing, empowerment and ultimately improve health. These may include providing social protection benefits such as sick pay, holiday pay, maternity leave and encourage personal development. Individuals can be benefited, of course, by having the education and skills that give them the opportunities for more satisfying work. More generally, reducing the numbers of people not in employment, education or training must be a task of government policy.

Education, income and material deprivation Studies have shown a correlation between education, income and material deprivation – the inability to afford goods or activities commonplace in society. Unsurprisingly, education appears to be a determinant of income and material deprivation a consequence. Material deprivation has been stated as the single most important determinant of life expectancy.

Therefore, improving education and income are both key to tackling inequalities in life

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expectancy. Associations found between low income and adverse health behaviour, supports this further. Improving income via welfare payments has a large impact where people are below the minimum income standard, in or out of work. The more generous a country is with its welfare payments the narrower the health inequalities.

What are we doing to close the health gap?

As it stands, the gap in life expectancy between areas of high social deprivation and those of high wealth in increasing. The Institute of Fiscal Studies has estimated that as a result of tax and benefit reforms instigated by the current conservative government, families with children are projected to sustain big losses in income – the lower the income, the greater the loss. At the onset of the global financial crisis in 2008, 39% of families fell below the minimum income standard. By 2014, this has risen to 45%.

Furthermore, funding to local authorities has been cut sharply, causing their spending power to reduce by 23% between 2009 and 2014.

Local authorities are responsible for providing services to support families, therefore these actions have led to the closure of key children’s centres throughout the country. Additionally, government grants were cut by 39% per person in real terms. Each of these is likely to contribute to increase in health inequalities.

Together, they make the task of local action, particularly in deprived areas, much more difficult.

To conclude, society has a moral responsibility to improve health equity throughout the country. Health inequalities are not an inevitable scenario, and can be tackled from multiple different angles. It is not just the responsibility of the healthcare sector to reduce health inequality in the UK. A greater political will from both the government and society as a whole is required.

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IN FOCUS

The bumblebee sweet tooth Ashwin Miriyala

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he sense of taste, or gustation, allows an animal to find nutrients that are essential for survival. For bees, the gustatory system plays an important role in detecting the hundreds of different compounds that comprise nectar, including sugars, salts, amino acids, minerals, water and lipids. But how does the gustatory system perform such a complex task?

Well, it turns out that this, at least in part, is due to significant organization of gustatory machinery at the periphery. Gustation starts within cylindrical structures called sensilla, which are akin to the taste buds in humans and other vertebrates and are distributed on the mouthparts of the bee. Each sensilla house the dendrites of 4-5 gustatory neurons, whose role is to translate the tastant information into a sequence of action potentials that are transmitted to the brain. Remarkably each gustatory neuron expresses a subset of gustatory receptors that only bind to tastant molecules of a specific taste category. In this way, each bee gustatory neuron will respond to either sweet compounds, low concentrations of salt, high concentrations of salt, bitter compounds or water.

Therefore, the organisation of receptors and gustatory neurons allows the peripheral taste system to efficiently classify the hundreds of different taste compounds into 5 different categories. This is surprisingly similar in vertebrates, where individual taste cells within the taste buds express receptors that bind to molecules belonging to one of the five well known taste categories; sweet, salty, sour, bitter com-

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pounds or umami (i.e. the taste of meats). In most insects and vertebrates, only a single gustatory neuron in each sensillum or taste bud will be activated by tastants from a specific taste category.

How does the gustatory system perform such a complex task?

The gustatory neurons encode these tastants through simple patterns of action potentials, or spikes. This can be described as a rapid (order of 0.1 second) increase in spiking rate from a near silent baseline, followed by a gradual decrease in spiking rate (order of 1 second) as the gustatory neurons adapt to the stimulus. The rate of spiking itself is dependent on concentration of the stimulus. Thus, the rate of spiking of individual gustatory neurons carry information about the taste category and concentration to the brain, where appropriate behaviours are coordinated.

However, our research at Newcastle University showed that studying taste in bumblebees reveals that the peripheral taste system can show additional features that contribute to coding efficacy. Using electrodes to record from the bumblebee Bombus terrestris mouthpart sensilla, we found two gustatory neurons within

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each sensillum that are activated by distinct concentrations of sweet compounds. In response to sucrose for example, the first neuron is found to be more sensitive and exhibits spiking above 5 mM, whereas the second neuron is only activated above 25 mM. The rate of spiking for both these neurons reaches a threshold at around 100 mM. Further, the activation of the second sugar neuron effects the overall spiking pattern measured from each sensillum. Whenever the second neuron fires an action potential, the first neuron is inhibited for a brief period of time (~0.03 seconds). As a result, the code for sucrose for the bumblebee gustatory neurons looks like a burst firing of action potentials; the first sugar neuron keeps firing rapidly until it is shut off by a single action potential from the second neuron. This is the first time that such a consistent pattern has been observed from any gustatory neurons.

For the bumblebee, we found that the ~0.3 second inhibitory periods could be described via what are known as gap junctions, i.e. protein channels that allow flow of ions and other molecules between neighbouring neurons. Indeed, blocking these gap junctions using the inhibitor carbenoxolone resulted in only the first sugar neuron firing rapidly with sucrose stimulation, which levelled out to a baseline firing rate within 2 – 3 seconds.

How could this burst pattern mediated by gap junctions help in gustation? Incredibly, our research found that when the sugar neurons exhibited bursting, the first neuron exhibited a rapid spiking for up to 10 seconds before reaching the baseline firing rate. This indicates that the inhibition provided by the second neuron allows the first neuron short intervals of time to ‘rest’, allowing it to fire faster for longer periods of time.

Coupling these data with behaviour revealed that bees naturally spend between 7-10 sec-

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onds on their initial contact with nectar. It is likely then that bees have developed burst firing as a method to resist adaptation in neural spiking rate; a continuous high spiking rate would drive a persistent feeding on nectar. This is advantageous as it allows the bee to utilize every food source it finds, hence burst firing is a logical adaptation for an animal that collects food for its entire colony. In fact, we found similar bursting in several other species of bumblebees and honeybee gustatory neurons as well, which could indicate a general evolutionary strategy in this family of insects.

These findings indicate that interactions between neurons, in this case through gap junctions, can provide a beneficial modification of the gustatory code. Given the similarity in the taste system between invertebrates and humans, these results combined with ongoing research into invertebrate gustation, could reveal important insights into how taste works in humans. Even further, studying the mechanisms of neural coding in insects like bees can help us discover other strategies that neurons within our brains use to encode environmental stimuli and process data within neural circuits.

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OPINION

From household pests to superheroes the common fruit fly!

Charlotte Graham

F

or the past three years I have encountered the following conversation countless times; ‘What’s your PhD in?’

‘I’m looking at ageing using flies’ ‘Flies?!’

Cue that all too familiar look of confusion..

I agree. It does seem bizarre that a small insect would have any biological relevance to the human body. However, there are many reasons that make our fruit fly ‘Drosophila Melanogaster’ an incredibly valuable model for ageing research. Despite the lack of resemblance, Drosophila can overcome many limitations that other scientific models, such as mice and cells, may face. Not to mention the six Nobel prizes awarded to fruit fly research, most recently being last year.

Allow me to convince you further:

whole organism and observe interactions of all the components that make up a complex living thing.

For instance, imagine a car. Cars are made up of lots of different components that all work together to allow the car to drive. There is the engine, wheels, exhaust pipe, brakes, gear box, clutch etc. This is similar to a human body in that a change to one part could cause a change in how all the other different parts function.

Therefore it is important to take all of these into consideration, rather than looking at a single cell we should look at an entire organism.

We’re not as different as you think.

Wings, six legs and a penchant for mouldy fruit aside, a lot of processes which happen in our bodies also take place in the fruit fly and there are closely related fly genes for over 70% of disease genes.

It’s important to look at the whole picture.

Using Drosophila allows us to carry out many experiments in vivo. In vivo translates from Latin as ‘within the living’ as opposed to in vitro which translates to ‘in glass’. In scientific terms they do exactly what they say on the tin. In vitro experiments look at isolated components of an organism such as cells which are grown literally on glass (or plastic). Here limitations can arise as the surroundings are artificial and sometimes results can lack biological relevance.

In vivo experiments however, let us look at a

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For example, in humans the gene PINK1 has been found to be mutated in many inherited cases of Parkinson’s disease. When PINK1 is mutated in Drosophila they also display movement defect symptoms – that’s right, flies get Parkinson’s.

urgency to understand the mechanisms behind ageing, now more than ever. By understanding what makes flies live longer or die younger we can find solutions which facilitate healthy ageing and prevent the onset of age-related diseases.

This is extremely useful for modelling specific human diseases in flies so we can study – in vivo - the mechanisms behind them in the hope of discovering future treatments.

Cheap and low maintenance – the perfect date.

Fruit flies have contributed vast amounts of scientific data Practice makes perfect.

Fruit flies were first introduced to genetic laboratories in the 1900’s. Therefore, we’ve had a lot of time to understand their genome – 100 years to be exact. You can think of a genome like an instruction manual, everyone has one and it is personal to each animal. During this time and due to their small genome, scientists have been able to map out the entire fly genome and design a seemingly limitless list of genetic tools. Nowadays, we can easily manipulate the genome by removing, mutating and adding genes from other animals which otherwise may be too expensive and time consuming to conduct in other animal models.

Short but fruit-full lives.

The average fruit fly lives 2-3 months, making them particularly ideal for carrying out lifespan studies quickly and easily. In comparison to, the average 3 year lifespan of a mouse making them undesirable participants.

Our population is ageing rapidly, meaning an increasing number of people are developing age-related diseases therefore it is a matter of

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Finally, fruit flies cost little to keep and maintain. Certainly compared to humans they take up less space and are available in much higher numbers, allowing us to carry out as many biological repeats as possible. As famously stated in Mean Girls “The limit does not exist!”.

Additionally they come without the ethical concerns other animal models face. (Less paperwork for us!).

How does this all benefit my research?

Reactive Oxygen Species (ROS) are generated as our cells produce energy. At low levels they are important for keeping our cells healthy however, once they reach a certain limit they can be harmful.

Over the years research has indicated that levels of ROS increase as we age. In my PhD I use flies to study the impact of ROS production during ageing, whether it is good or bad. I have been able to take full advantage of all the great stuff flies have to offer in hope to further understand what really does go on during ageing and how we can prevent the associated diseases occurring.

So apart from providing me with some fairly unusual first date conversations, fruit flies have contributed a vast amount of valuable scientific research across a wide range of disciplines, including ageing. Continuously proving that there are few limitations to their application within research.

After all, if Marvel’s Antman can help save the world – why can’t the humble fruit fly?

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IN FOCUS

Red alert for our blue planet Ella Brunt

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he Earth may be hurtling towards great natural disaster, climate scientists have warned. They fear a new cut in the limit of the planet’s tolerance to rising temperatures means the crisis might come much sooner than expected.

A ground-breaking report by the United Nations Intergovernmental Panel on Climate Change (IPCC) says the limits of the Earth‘s tolerance of rising atmospheric temperatures must be reduced by half a degree lower than previously predicted. This means that the planet can only sustain current life if the climate does not warm by more than 1.5°C. The 33-page report encompasses 6,000 references and has 133 contributing authors, making for a significantly comprehensive study of climate data. Amongst the IPCC board members, chief negotiator for the alliance of small island states, Amjad Abdulla, has highlighted that the world has “the slimmest of opportunities remaining to avoid unthinkable damage to the climate system that supports life as we know it”. Jim Skea, Co-Chair of IPCC Working Group III, believes that the proposed limits are possible, however this would require “unprecedented changes” to the global fuel economy.

Previous climate research from the past 10 years has failed to predict the true trajectory of global warming and, until this revolutionary report, the climate limit was set at 2°C. Therefore, the current plans to mitigate global warming are not sufficient to reach the previous temperature goal, meaning

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substantial changes are required to remain below the new limit.

The report proposes four pathways to achieve the 1.5°C limit, including a reduction in the use of fossil fuels, particularly coal, which has been labelled as the biggest source of carbon emissions. In order to achieve a carbon-neutral Earth with manageable levels of carbon emissions, current global coal consumption must decrease by two thirds. Whilst also a fossil fuel, natural gas is thought to produce only half as much carbon dioxide as coal, and therefore many countries have seen a shift in energy sources from coal to gas. However, it is believed that natural gas is only a ‘bridge fuel’ until alternative energy sources are found, and cannot be relied on indefinitely. Moreover, natural gas drilling results in methane leakages that further contribute to greenhouse gas emissions. This means that more widespread use of renewable, clean energy sources is vital to meeting the new 1.5°C target.

In 2015, the U.N. set 17 Sustainable Development Goals (SDGs), with 169 individual targets to alleviate social, environmental and economic development issues. One of these goals was to "take urgent action to combat climate change and its impacts by regulating emissions and promoting developments in renewable energy."

This puts immense pressure on the oil and gas industry to work towards more environmentally sustainable energy. Other blogs.ncl.ac.uk/react

goals aim to eradicate poverty and to provide affordable and clean energy worldwide. By expanding the distribution of fossil fuels to developing countries and small island nations, further action will be needed to mitigate carbon emissions. It is therefore crucial that replacement renewable, clean energy sources are established.

The US president’s talks of withdrawing the US from the Paris Agreement (the first global climate change agreement) could have monumental effects on the proposed actions to combat rising temperatures. The US represents the second highest contributor of carbon dioxide emissions, behind China. Brazil, the sixth biggest emitter of carbon emissions is also rumoured to be poised to leave the Paris agreement since the October Presidential Elections saw Jair Bolsonaro come into power.

All members of the Paris Agreement are under jurisdiction to outline, plan and report targets that moderate their contribution to global warming. Members classed as ‘developed countries’ are also expected to help fund developing nations’ to achieve climate change adaptation and mitigation, as part of the Green Climate Fund. Therefore, if these nations leave the Paris Agreement, it could make meeting the 1.5°C limit even more challenging. The upcoming 24th Session of the Conference of the Parties (COP24) to the United Nations Framework Convention on Climate Change (UNFCC) in December, will therefore be instrumental in influencing the creation of new

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targets and alliances to reach the 1.5°C goal.

Those countries making the smallest contributions to carbon emissions are often worst-affected by climate change. The Maldives is set to be mostly uninhabitable by 2050 due to rising sea levels. Honduras was named as the most affected nation by climate change in a 2017 report by the Global Climate Index. It experienced 61 occasions of extreme weather since 1996, despite contributing only 0.1 % of global greenhouse gas emissions in 2013, according to USAID. Recent extreme weather events such as the tsunamis in South East Asia and hurricanes across the Caribbean nations have also been attributed to global warming.

Developed countries are not immune from these greater instances of extreme weather. In the last few years, wildfires have ravaged Portugal and California, and widespread flooding and landslides have swept across the central US. The US president, Donald Trump, infamously said, “Man, we could use a big fat dose of global warming!”. However, experts believe temperature increases exceeding 1.5°C could lead to frequent extreme weather events, the loss of several keystone species in marine and terrestrial environments, as well as the displacement of human populations and increased poverty. With the Earth currently on course for a 3-4°C hike in temperature by 2100, the report highlights that global warming is happening now and a global effort is essential to protect all forms of life on our planet.

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REVIEW

Book review

Origin Emma Kampouraki Dan Brown employs his favourite fictional Harvard professor of religious symbology once again. Robert Langdon visits the ultramodern Guggenheim Museum at Bilbao, Spain for an event that promises to ‘’change the face of science forever’’. The battle between religion and science has begun.

W

here do we come from? Where are we going? Two fundamental questions of

human existence that are to be answered in a public announcement by Edmond Kirsch, a renowned billionaire tech genius and futurist, before Edmond is assassinated in front of millions of online viewers around the world, preventing him from doing so.

Kirsch’s presentation had promised to elucidate the mystery of life and make all the world’s religions redundant at a stroke. Robert Langdon is accompanied by the elegant Ambra Vidal, museum director, and future Queen of Spain, as he flies to Barcelona to crack Edmond’s

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password and enable them to project his presentation around the globe.

This novel, although much criticised for its low editing standard and its ‘over-egged resolution at the end’, described the incompatible relationship between science and religion and their greatest debates that still cause a schism.

The birth of our universe according to religion has long been questioned in light of recent scientific theories, based on the observation of the universe’s current expansion and relevant extrapolations.

An enjoyable blend of ethical problems and futuristic scenarios is confronted to the

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backdrop of the Royal Palace of Madrid, a place rich with history and religion. At the same time, Edmond’s quantum-computer artificial intelligence (AI) assistant, Winston, offers a great example of how technology could really transform the way we perceive relationships and communication in the future. Brown, deeply fascinated by the topic of AI, explores its potential to solve humanity’s greatest problems and yet posits that it has become so powerful that it could destroy us if weaponised. With the ability of Winston to read the patterns of our digital-centric culture and its interaction with humans, Brown touches upon the popular, outdated belief that AI could learn compassion as well as self-centred evil against humanity’s interest.

Ambra serves as the “human” element of the story, in contrast to Winston’s “artificial” element and her very human attention to detail is key in her ongoing quest to communicate Kirsch’s discovery to the world. Langdon, by comparison, uses his wealth of symbology experience to interpret the clues leading to the controversial presentation’s password.

Incorporating immersive comments from the world of social media and an incredibly wellstructured, thrilling plot with no loose ends, Brown exceeds the expectations of his fans this time and uses his talent to discuss and break

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Brown, deeply fascinated by the topic of AI, explores its potential to solve humanity’s greatest problems down established barriers between religion and science. Even if you manage to guess the twist, even if you hate Brown’s ‘formula’, you’ll still reach the end with a sense of relief and enjoyment. There are still puzzles to be solved while Langdon gets to know better other characters- a similar approach to other books in the Langdon series. However, this ‘journey to the modern world’ comes without much cryptography and symbols, which could be the novelty that will keep non-fans interested till the last pages.

Origin topped the New York Times Adult Best Seller Lists for 24 weeks upon publication and has been complimented for focusing on "serious ideas" relating to the co-existence of religion and science. It could be Brown’s most captivating and fascinating novel to date.

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FUN AND GAMES

Fun and games Christina Julius

Word search

BREACH BREXIT BUMBLEBEE CATASTOPHE CHEMOTHERAPY CLIMATE CLINICAL DEHYDROGENASE DROSOPHILA ENZYME

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EUROPE FAILURE GAME GOVERNMENT GUSTATION HIGH ISSUE LIMIT LOW MAY

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METHOD MICROSCOPE MORBIDITY NEURON ORANGE PATHOGEN PAYMENT PHYSIOLOGY PROCESS RAIN

SCIENCE SENESENCE SUCCESS TOXIN TRUMP VACCINE WATER

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