CONTENTS
Nobody said changing lives was easy.
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Editorial
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News
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News in Focus
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Photo Competition
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PharMANcology
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Cancer Immunotherapy
STAFF LIST Editors-in-Chief: Vicky Pike & Jess Gorrill Deputy Editors: Josephine Pepper (Print) Daniel de Wijze (Web and Blog)
Join our Leadership Development Programme and help end educational inequality.
10 Spotlight on: Zika
teachfirst.org.uk/recruitment
12 Nuclear Solutions to a Nucleic Problem
Creative Director: Ruby O’Grady Sub Editors: Jack Cooper Thomas Player Hannah Sharpe Rachel Kealy Jiaxen Lau Utsav Popat Adam Bendall Kushal Mansatta Xanthe Gwyn Palmer Rosemary Chamberlain Hugh Evans
14 Absolutely FAD-ulous 16 Home Remedies Expose 17 Viral Vecored Vaccines 18 Interview with Adrian Hill 21 Pain Prevention 22 Calling time on The Obesity Epidemic 24 Interview with John Parrington 26 iGEM searches for a Cure
Maksim Mijovic Management Consultant, PwC Taught: Maths
Teach First is a registered charity, no. 1098294
27 Student Showcase 28 Book Review
Published by Oxford Student Pulications Limited
Artists: Ruby O’Grady Gulnar Mimaroglu John Molesworth Sophia MalandrakiMiller Holly Rutherford Business Director: Emily Fay
Chairman :Steven Spisto Managing Director : Josh McStay Finance Director :Tom Metcalf Company Secretary : Tom Hall Directors :Mack Grenfell, Sophie Aldred
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Life-Changing Careers at Oxford BioMedica
EDITORIAL
Oxford BioMedica is a pioneer of gene and cell therapy, with a leading position in lentiviral vector therapy research, development and manufacture. We were founded in 1995 as a spin-out from the University of Oxford’s Department of Biochemistry.
The Ancient Greeks believed men could heal their ailments by sleeping in the Asklepeion for a night. It is a common joke to chastise Medieval medicine men for believing a leech could cure a headache. Nowadays, our remedies are far more precise.
Our world-class lentiviral vector research and development, analytics and cGMP manufacture is helping deliver the future of medicine
Viruses, bacteria, parasites that once held power of life or death over humanity, such as smallpox, now exist only in dusty history books. Yesterday, remedies were essentially guesswork; today we live on the cusp of personalised medicines tailored to our individual genomes. It is inherent in human nature to strive for better. From the Greek physician Galen describing a tumour for the first time in the second century AD to Louis Pasteur striving to provide the world with the first advances in vaccination, the pursuit of a better scientific understanding of our world and of our diseases has been a constant throughout history, and will continue as such for centuries to come.
Our mission is to build a leading, profitable biopharmaceutical company founded on the successful development and commercialisation of breakthrough gene and cell-based medicines. Through our in-house research and product development programmes, and collaborations with leading academics and industry partners, our goal is to improve the lives of patients all over the world with debilitating and life-threatening diseases whilst creating shareholder value.
We were the first in the world to administer a lentiviral vector gene therapy product directly to patients We are headquartered in Oxford, UK where we operate multiple manufacturing facilities. At our new head office, Windrush Court – we have just completed extensive refurbishment including the creation of world class laboratories.
We have cGMP approved manufacturing facilities, with process development, industrialisation and analytical capabilities
This is a consistent theme in this term’s issue of Bang!, in our interview with Adrian Hill, a leading mind in the development of the Ebola vaccine (page 18), in our piece on the Zika virus (page 10), and in our piece on bacterial resistance to radiation (page 12). Make sure you check out our interview with the fantastic John Parrington on his new book (page 24) and the fabulous entries from students around Oxford in our scientific photography competition (page 6) as well. While scientific progress has leapt ahead in the last decades though, it is undeniably wrong to equate recent progress with any sort of finish line being crossed: as Adrian Hill put it, “the biggest challenge is the unknown”. Even this issue’s piece on bacterial resistance to radiation highlights that while we are masters at adapting to challenges, the challenges themselves are equally adept at adapting to us. As ever, enjoy this term’s issue of Bang!
Jess Gorrill and Vicky Pike Our partners include Novartis, Sanofi, GlaxoSmithKline and Pfizer, as well as charitable organisations, such as the Foundation for Fighting Blindness, Cure Parkinson’s Trust and the UK Motor Neurone Disease Association
Editors In Chief
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NE WS NEWS IN BRIEF
NEWS IN FOCUS Back in February 2015 there was a great deal of excitement surrounding the development of pre-exposure prophylaxis (PrEP), a drug with the potential to control the spread of human immunodeficiency virus (HIV).
Walking on Sunshine Solar Impulse 2 has become the first aeroplane to fly around the entire globe with no fuel, using only energy from the sun. The plane, which completed the epic 40,000 km journey in July, has a wingspan larger than a Boeing 747 in order to accommodate the 17,248 solar cells which keep it aloft. Amazingly, despite this massive size, it weighs just 1600kg, about as much as a minivan. Swiss pilots Bertrand Piccard and Andre Borschberg successfully guided the plane around the world from its starting point in Abu Dhabi. They made 16 stops along the way, but had to fly across the Atlantic and Pacific oceans in one trip. In order
to save energy during the ocean crossings they would charge the plane during the day, and fly at just 1500 metres during the night. On the way they broke eight world records, including becoming the first pilots to fly a solar powered plane for a whole night by using energy stored in the plane’s batteries. Whilst Solar Impulse 2 had a rather limited top speed of 30 mph and took over a year to complete the circumnavigation, Piccard and Borschberg hope that their adventure lays down a marker to the aviation industry of the incredible potential of solar power. In years to come we may glide across the skies using no fuel at all!
Cruelty free or fowl and unnatural? In the UK we eat over 70 million chickens each month, but would you consider eating chicken grown in a machine? Professor Yaakov Nahmias of Hebrew University Jerusalem has invented a method of ‘growing’ meat that could lead to a ‘chicken machine’ in every restaurant and supermarket. Nahmias has dubbed his creation ‘SuperMeat’, in the hope that it can contribute towards reducing the huge environmental strain of meat production, whilst helping to solve the mammoth task of fighting world hunger.
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In the SuperMeat process, a small tissue sample is harmlessly taken from a healthy chicken and placed in a specially designed ‘nutrient soup’. The cells grow into tissues within a carefully controlled environment, eventually forming pieces of meat that are ready to eat.SuperMeat co-founder Koby Barak—a strict vegan and an animal rights activist—hopes that artificial meat is an acceptable, cruelty free solution for vegans that finally allows them to enjoy a chicken sandwich without guilt.
“Lack of treatment meant that HIV was a death sentence”
Scientists fear for their funding post-Brexit Many researchers across the UK have already reported losing opportunities for new research grants just one month after the country’s referendum to leave the European Union. Currently the EU contributes £850 million each year towards research funding in the UK, but much of this money is under threat, with new applicants for grants reportedly facing rejection. Flagship research programmes such as the Horizon 2020 project, which aims to ensure high quality scientific research in Europe, are reluctant to provide funds to a country that now wants less integration with the continent. In addition, UK universities may face losing out on the best European academic talent as well as the ability to collaborate effectively with their counterparts on the continent.
However, Sir John Kingman, head of the new UK Research and Innovation group (UKRI), has encouraged scientists to place research at the front of the new economic plan for the UK outside of the EU. The UKRI has been set up to coordinate the nine funding bodies that support UK research and controls £6 billion of funding each year. In addition, new Prime Minister Theresa May has stated that her government’s “ongoing commitment to science and research remains steadfast”. With an extra £500m needed per year to make up the shortfall many scientists remain sceptical, but perhaps there is hope for the science community in this new Brexit world.
by Daniel de Wijze
HIV spreads predominantly through unprotected sex with an infected person and works by slowly destroying the body’s immune system, leaving the sufferer vulnerable to infections which healthy individuals could shrug off. The virus does this by entering cells in the immune system called CD4+, which protect the body against various bacteria, viruses and other germs. It hijacks the CD4+ cells and uses them to make thousands of copies of itself, killing them in the process. Over time, the number of CD4+ cells drop so low that the immune system stops working, leading to the final stage of the virus, called AIDS. For many years, lack of treatment meant that HIV infection was a death sentence. As the years passed, drugs were developed which allowed HIV sufferers to live longer, healthier lives. But the catch is that these drugs are very expensive. Treating one person over their lifetime costs the NHS approximately £360,000. An alternative was suggested: antiretroviral drugs. These are taken by uninfected individuals, giving resistance against
HIV infection. When PrEP arrived on the scene offering just that there was elation in the medical world and from high-risk communities such as gay men and sex workers. PrEP has the potential to drastically improve the lives of individuals at risk, many of whom are already stigmatised.
of the furore, to offer fairer prices for their drug. Whether they will agree to do so is unclear.
There was one problem. NHS England refused to fund the drug. The decision outraged charities such as the National Aids Trust (NAT), but the NHS defended its position, describing PrEP a ‘preventative’ drug, and calling for local authorities to fund it as part of their public health role. In turn, local authorities announced that they had no money to achieve this, citing huge budget cuts that began in 2013.
In August 2016 the High Court ruled that the NHS should pay for PrEP, a decision celebrated by AIDS campaigners across the country. The chief executive of NAT described the ruling as “vindication for the people… let down [by] NHS England.”. The NHS has set aside money for PrEP, which is estimated to cost £10m-£20m, but the drug will still have to be considered with others competing for the limited funding.
The decision by the NHS may seem controversial, but the organisation is struggling after its own brutal budget cuts. Money spent on HIV prevention means a reduced budget for funding other new drug treatments. In addition, opponents of PrEP feel unwilling to fund a drug that may encourage users to have unprotected sex and could potentially lower condom usage. Supporters argue that by reducing the number of new infections each year, the NHS saves itself the cost of providing care for the whole life of an infected individual—a more sustainable long term solution.
“NHS England refused to fund the drug”
The situation is made more difficult by Gilead Sciences, the company that manufactures PrEP (under the brand name Truvada). The NHS have asked the pharmaceutical company, who have mainly avoided the brunt
The solutions to these problems lie with scientists and their ability to work with both politicians and social scientists. In the meantime, the fight to eradicate HIV and the suffering it causes goes on.
There is also an added layer to the debate. Does the NHS have an ethical responsibility to fund the drug and avoid potential HIV cases that could be prevented?
The arguments around the necessity of PrEP continue to rage, but the case raises many important arguments about public health and the difficult decisions that must be made. Should we focus on cure or prevention? How do we decide which drugs receive funding? Does society have a responsibility to fund all breakthrough drugs, no matter the size of the community they benefit?
ph oto compe tition
WINNER
by Chevonne van Rhee
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Tracing of brain regions on a sagittal T1 MRI scan for the Neurosim project, a learning tool being developed by Nuffield Dept. of Clinical Neurosciences designed to help medical students as well as clinicians learn structural and functional neuroanatomy
OTHER ENTRIES Gulnar Mimaroglu, Christopher Woodham, Martyna Zelek, Ollie Braddy
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PharMANcology? Should prescriptions account for sex? In 1993, the World Health Organisation distributed a measles vaccine in rural Senegal to aid a disease outbreak. The results shocked the medical community: the vaccinations resulted in an increased mortality rate amongst girls compared to boys receiving the same vaccine. It is surprising that a difference as biologically significant as sex could have been overlooked for so long.
“the vaccinations resulted in an increased mortality rate amongst girls” Female vertebrates have a stronger immune response than their male counterparts. This is thought to stem from the different sex hormones circulating in their bloodstreams. Oestrogen, a female sex hormone, is found to have an important protective effect. Studies show women who produce less oestrogen, but who have normal levels of other hormones, have weaker immune systems. It is thought that T-cells, which affect the immune response, may be more responsive
to oestrogen than male sex hormones. Furthermore, the ability of organisms to respond effectively to infection by pathogens is closely linked to the expression of diseaseresistance genes. The expression of genes is the synthesis of proteins from them. Sex hormones may affect the expression of genes linked to the immune response, for example of genes coding for proteins in the major histocompatibility complex, which prevents pathogens from entering cells. Sex hormones also affect how individuals behave. Testosterone increases aggression and competitiveness in males which, although evolutionarily justified by an increased likelihood of finding a mate, is thought to expose them to more pathogens. But it is not just the difference in ability to respond to pathogens that is different between sexes. Many studies have found that women have a lower pain threshold— in other words they can endure lower levels of pain—than men. They attributed this to three main factors: hormonal differences, the increased density of sensory receptors in women compared to men, and the differences between the physiology of the male and female brain. This research
is in stark discordance with the common assumption, present even amongst medical personnel, that women are better at managing pain than men. Indeed, in a study by McCaffery and Ferrell of over 300 nurses, the majority believed women were better at managing pain, while men in pain needed more time and efforts dedicated to them. Another jarring fact coming from research in the medical field is that women’s pain is not perceived to be the same as that of men, or not responded to in the same way. Feminist literature claims that women’s voices are seen as irrational and overly emotional; perhaps it finds foundation in the fact that women with chronic pain are more likely to be diagnosed with histrionic disorders than men with the same pain. Women are also more likely to be prescribed sedatives (to calm) rather than analgesics (to treat pain). There seems to be an assumption within the research community that the hormonal changes during the menstrual cycle make females less suitable subjects in clinical trials, and this assumption seems to be impervious to empirical disproval. such. W In 1993, the National Institute of Health wrote the Revitalisation Act to tackle gender bias in research. However, a study in 2009 found only a small minority of clinical-trials on mammals report the animals’ sex. When sex was reported in some fields, such as neuroscience research, the bias was as high as 5.5:1 towards non-human male mammals. In 2014 the NIH wrote more regulations to reduce this bias in animal models, but is this enough?
“Women are more likely to be prescribed sedatives (to calm) rather than analgesics (to treat pain)”
Immunotherapy – harnessing the body’s inner strength Helping the Immune System win the War against Cancer Cancer is one of the biggest causes of death worldwide and 14.1 million people are diagnosed every year. Despite this, treatments of cancers remain archaic, with chemotherapy and radiotherapy having highly unpleasant side effects due to their low specificity to cancer cells. The development of cancer immunotherapy has been touted as the most promising cancer treatment approach in decades and is said to have the potential to revolutionise cancer treatment.
“it has the potential to revolutionise cancer treatment” The immune system is able to detect and destroy abnormal cells, preventing the development of many cancers. Cancer cells expressing a unique tumour antigen protein on their cell surface are recognised by cells of the immune system, which stimulates B cells to produce antibodies. These antibodies bind to the tumour antigen and initiate destruction of the tumour by cytotoxins produced by more white blood cells—T cells and natural killer cells. This is the natural immune response to the presence of cancer cells in the body. Since DNA mutations occur at high rates in cells, the immune system destruction of potentially harmful cells occurs very often, thus protecting individuals from cancer.
However, some cancer cells are able to avoid detection by the immune system and it is these cells that will eventually become cancerous. This is thought to occur by a range of mechanisms. Immunoediting escape occurs, for example, when cancer cells are able to suppress the immune system through producing their own regulatory T cells (which ordinarily act to protect ‘self’ antigens from the immune system) and stimulating the release of immune-suppressive cytokines. Furthermore, some cancer cells do not present a tumour antigen and so go unrecognised by antibodies. These unregulated cancer cells grow and metastasise and demonstrate a form of Darwinian natural selection—survival of the fittest amongst the cancer cells. Cancer immunotherapy is designed to counteract these cancers’ suppression of the immune system and to increase the strength of the immune system against tumours. This is in contrast to common cancer treatments such as chemotherapy, which kill cells of the immune system along with tumour cells. This prevention of immune suppression from the cancer cells can be engineered using monoclonal antibodies against regulatory T cells, causing increased regulatory T cell destruction and promoting tumour cell elimination. New work in this field is developing forms of vaccination therapy, such as using a vaccine based on peptides derived from tumour-associated antigens. These peptides could allow the individual to
mount an immune response, and to then use these antibodies to target tumour cells in the body. Though tested only on a limited number of patients, vaccination therapy showed partial or complete tumour regression in 10-30% of patients. Additionally, immune therapies based on monoclonal antibodies are being developed. These use recognition of cancer cell surface proteins other than the tumour antigens. Results from patient trials have been described as ‘very encouraging’, with 20% of advanced melanoma patients completely cured of tumours.
“cancer demonstrates a form of Darwinian natural selection” The potential of cancer immunotherapy is huge due to its ability to target cancer cells specifically, resulting in fewer side effects. This treatment can be applied nearly universally and may provide immune ‘memory’, meaning the individual remains protected after treatment ends. While a great deal more work is required before this treatment becomes widespread, it could prove to be a hugely powerful weapon in the on-going war against cancer.
by Adam Bendall Art by Holly Rutherford
The danger posed by gender bias in clinical trials is exemplified by studies on antiretroviral drugs. when these drugs, which had been approved for men and assumed to work for women, were given to HIV sufferers, adverse side-effects were more common amongst women. Perhaps it is overly dramatic to claim that female health has not been as interesting to researchers as men’s health. On the other hand, we must agree that change is needed to tackle the apparent sexism in medicine; outdated prejudices must be abandoned in the face of empirical findings in order to ensure healthcare is optimised for all.
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by Elena Zanch Art by John Moleswoth
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Studies quickly confirmed that ZIKV could infect progenitors in cultured cell lines, but the slow growth of mature neurons delayed progress. Three months later, the results came in—mature neurons seemed resistant to ZIKV infection. Despite the hype, this could tell us nothing about why ZIKV easily infects progenitors but not adult neurons.
SPOTLIGHT ON: ZIKA
Delving below the headlines to see what the science actually says On November 17 2015 the Brazilian Ministry of Health issued a statement that would instil panic in a country where abortions are almost always illegal and contraception is hard to come by: rates of microcephaly were soaring. Scientists scrambled. The American Centers for Disease Control and Prevention became convinced that a previously apparently harmless infectious agent, the Asian strain of Zika virus (ZIKV), was the cause. The Olympics were at risk of postponement. Zika spread to North America, Africa, and Asia. Genetically modified mosquitoes were released. Vaccines entered clinical trials. Pharmacologists identified potential drugs. One year on, what is the evidence that leads us to claim causation, and how does this fit in with our current knowledge of brain development?
and brain tissue of miscarried and stillborn foetuses affected by microcephaly. Further studies in Brazil linked ZIKV infection in pregnancy to infant microcephaly, and women who recently travelled to areas with active ZIKV transmission have borne microcephalic infants. A similar pattern of cases can be charted in French Polynesia, a country affected by a Zika outbreak in 2013-14.
“what is the evidence that leads us to claim causation”
During pregnancy, the upper part of the foetal cranium (the calvarium) expands as pressure builds inside it to accommodate the growing brain. If the pressure remains low, as when the brain is undersized, the calvarium stays small, producing the characteristic ‘small-headed’ appearance of the microcephalic infant.
th
ZIKV is a virus transmitted by Aedes sp. mosquitoes, sexual intercourse, blood transfusion, and, as revealed this year, from pregnant mother to unborn child. ZIKV was first identified in Brazil in January 2015. Nine months later, the authorities were alerted to a steep increase in the number of children born with microcephaly, a specific, rare phenotype with associated brain anomalies, defined by a skull circumference <31.9cm and <31.5cm for male and female newborns respectively.
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Since then, ZIKV has been identified in the placenta, amniotic fluid
Together, the Exposure to to cause
evidence is convincing. ZIKV seems sufficient infant microcephaly.
However, this picture is incomplete. How could ZIKV cause microcephaly? To answer this we need to examine how the foetal head grows to the correct size during normal development.
The brain itself develops from a sheet of neural epithelium. During the fifth week of development these cells divide and elongate to produce apical radial glia (aRGs), long cells that span the width of the developing cortex and attach to both the ventricular and basal surfaces. They act as both neural progenitors and scaffolds for migrating cells. As aRGs divide, they self-renew, differentiate to produce mature neurons and astrocytes, and give rise to intermediate progenitors.
These progenitors have different typical shapes and positions along the apical-basal axis of the cortex, so they are exposed to different signalling environments. Their self-renewal and differentiation produces mature neurons with lineage-specific fates. Increases in the number of aRGs will increase the surface area and subsequent folding of the cortex, whereas the production of intermediate progenitors will increase the cortical thickness. In this way, the cortex can reach the correct size and shape with the correct numbers of neurons. Many genetic, non-viral forms of microcephaly produce an undersized but well-folded cortex, suggesting a lack of intermediate progenitor cells. CDK5RAP2 mutations, for example, cause deviations in the cleavage planes of aRGs at cell division. This positions the daughter cells incorrectly, exposing them to abnormal signalling from neighbouring cells and promoting differentiation too early. Thus, appropriate intermediate progenitor production is prevented, explaining why affected brains remain so small but look otherwise normal. Conversely, most infants with ZIKV microcephaly have an abnormally smooth cortex and much smaller brains than infants affected by CDK5RAP2 mutations. This suggests that ZIKV can affect aRGs and massively reduce the number of neurons produced. However, adult nervous systems do not appear to be as severely affected by ZIKV, suggesting that it struggles to infect mature neurons.
The cell surface receptor AXL may hold the answer. AXL is expressed by few adult neurons but is found in high levels on placental tissue, neural progenitors, the lining of blood vessels, and astrocytes. As Professor Arnold Kriegstein and colleagues at UCSF found through in vitro investigation, obscuring the extracellular domain of AXL with an antibody can block the viral infection of astrocytes, suggesting that this receptor is required for ZIKV entry. AXL’s expression by many developing tissues could also explain why ZIKV affects more than just the foetal brain. In an ultrasound study of 19 microcephalic foetuses thought to be infected by ZIKV, most had additional central nervous system malformations and seven had extracranial anomalies, such as liver and blood disorders. Infections during the third trimester of pregnancy can also cause foetal brain damage, perhaps due to the infection and functional compromise of astrocytes. Astrocytes support neuronal survival, protect the blood-brain barrier, and contribute to information transmission in the brain. If they
die, brain tissue could become inflamed, causing the death of mature neurons. Once inside cells, ZIKV goes in for the kill. By activating a signalling pathway involving the innate immune system surface protein TLR3, progenitor cells have been observed to undergo cell cycle and gene dysregulation, culminating in their death. This depletes the progenitor population extensively, massively
“ZIKV could help to solve some of the biggest mysteries in neuroscience”
decreasing the numbers of neurons produced. In vitro, some antagonistic molecules that bind to TLR3 can block its activation to decrease the rate of cell death in ZIKV-infected cells.
As TLR3 is highly expressed early in brain development, with levels falling as more of the progenitors differentiate to become neurons, this might explain the relative severity of early infection. However, even with a TLR3 antagonist, the rate of cell death does not drop to normal levels, suggesting that ZIKV triggers more than one pathway to cause the demise of its host. With more pathways now coming to light, it seems that a lot more research will be undertaken before we truly understand the molecular mechanisms involved. Looking to the future, after Zika has been brought under control, a new fate could lie in store for ZIKV. “ZIKV could become a tool to help us understand more about human brain development,” Professor Kriegstein suggests. “If we can use the ZIKV to target specific progenitor cell populations in the developing brain of an animal model system or in an appropriate experimental preparation, we might be able to learn more about the processes underlying cortical expansion and folding.”. In shedding light on these elusive mechanisms, ZIKV could help to solve some of the biggest mysteries in neuroscience. Surprising as it sounds, our old foe could become our new best friend.
by Hannah Sharpe Art by Gulnar Mimaroglu
another
agent
to
protect
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proteins.
“this radiation resistance is a sideeffect of resistance to prolonged dehydration”
nuclear solutions to a nucleic problem How a bacterium’s DNA gives resistance to extreme radioation Bacteria suffer from poor public relations. Ask any member of the public which bacterial species they know of and it’ll read like the FBI’s most wanted list: E. coli, M. tuberculosis, V. cholerae... villains left, right, and centre. But for every villain, there’s a superhero. Extremophiles are organisms that thrive in environments harsh enough to kill everything else. Thermus aquaticus proliferates in the hot springs of Yellowstone, shrugging off temperatures of 70°C, while Chryseobacterium greenlandensis can live in ice blocks 3000 metres below the surface. Just as Batman would seem out of place anywhere but shadowy Gotham, and Spiderman far more likely to be swinging through New York’s skyscrapers than wandering through rural Texas, these bacteria’s powers have evolved over millions of years to suit their environment perfectly. And then there’s Superman, who is ridiculously powerful no matter where he is. Superman, otherwise known as Deinococcus radiodurans.
“conventional repair enzymes are still functional after irradiation” Deinococcus radiodurans can easily survive an acute 5,000Gy dose of ionizing radiation. To put that into perspective, human cells will be killed by 5Gy. This is absolutely fascinating from a biochemical perspective. How on earth can a cell survive such an onslaught?
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Radiation is the emission of energy. Ionizing radiation is that which has enough energy to liberate electrons from atoms. This can directly damage cell components, breaking the bonds that hold DNA and proteins together and altering their chemical structures. Luckily for DNA there exists a whole host of repair enzymes raring to patch it up, with different enzymes for each type of damage. This is hardly surprising given that genome stability and integrity is essential for survival. For instance, DNA ligases help repair breaks in DNA’s sugar-phosphate backbone by catalysing formation of phosphodiester bonds. Ionizing radiation can prove particularly deadly if it causes double-strand breaks— breaking the sugar-phosphate backbone on both strands of the helix—because repairing them may lead to sections of the genome being moved to the wrong place. At the levels of ionizing radiation that D. radiodurans can survive, it will have suffered so many of these double-strand breaks that its genome is essentially shattered. Hence it seems reasonable to think that D. radiodurans may have evolved a unique repair enzyme or biochemical pathway that allows it to repair DNA damage much more efficiently. Indeed multiple studies have shown DNA repair in our superhero to be startlingly efficient across a whole range of damage types. But whole genome comparison to other bacterial species showed that D. radiodurans possesses only the standard DNA repair enzymes. If the secret of extreme radio-resistance does not lie with unique DNA repair pathways, then where? The key lies with how proteins, including
the DNA repair enzymes, are protected from reactive oxygen species with unpaired electrons known as free radicals, which are generated by the action of ionizing radiation on water molecules. The inability of other organisms to protect their DNA repair enzymes from these reactive oxygen species is the root of their radio-sensitivity. Not only are free radicals highly reactive and damaging, oxidising the molecules they come in contact with, but in their destructive reactions they generate more reactive oxygen species in a cascade which only stops when they react with each other to form stable molecules where all electrons are paired. Proteins and DNA suffer immediate and unavoidable damage from free radicals generated in close proximity to them.
“for every villain, there’s a superhero” Rather than having a completely novel DNA repair system, D. radiodurans simply ensures that conventional repair enzymes are still functional after irradiation. Across different bacterial species, proteins in radio-sensitive species are much more vulnerable to free radical oxidation species than those of radioresistant species. It simply doesn’t matter how efficient your repair enzymes are if they have been rendered non-functional by an onslaught of oxidation. This is why only a few doublestrand breaks are enough to kill bacterial and eukaryotic cells after irradiation—nothing is being repaired. However, extraction of D. radiodurans repair enzymes showed that the enzymes themselves are not resistant to oxidation. D. radiodurans must be using
Antioxidants are molecules that act as reducing agents to prevent other molecules becoming oxidised, and to remove reactive oxygen species. The vast majority of species rely on antioxidant enzymes and, under most circumstances, these enzymes are sufficient to remove any reactive oxygen species produced. However, the effects of high doses of ionizing radiation overwhelm the antioxidants, meaning that DNA repair enzymes cannot be protected. D. radiodurans avoids this issue altogether by using manganese complexed peptides as antioxidants. Manganese is a transition metal that can exist in a number of stable oxidation states, from +2 to +7. In D. radiodurans’ antioxidant complexes manganese is primarily in the +2 oxidation state, meaning that the complexes have great capacity for countering reactive oxygen species. The power of these complexes was demonstrated by adding them to solution containing the enzyme glutamine synthetase, which is normally destroyed by 150Gy of ionizing radiation. The manganese complexes offered dramatic protection, allowing glutamine synthetase to survive 50,000Gy. Another factor contributing to the extreme radio-resistance of D. radiodurans is its tightly packed chromosomes, facilitating
repair of double-strand breaks by keeping DNA fragments within a small area, but this is simply a feature that allows the manganese complexes to better perform their function.
still recover the song without any errors. This would prove helpful in preserving information for future generations in a format that is resistant to the effects of radiation.
This superpower is not only interesting from a biochemical perspective, but also from an evolutionary one. How on Earth did D. radiodurans evolve such a degree of resistance, when the highest known background radiation level is only 260mGy per year? Such low levels of exposure would have never driven selection for traits that promote resistance to ionizing radiation. Mattimore and Battista (1995) have suggested that this radiation resistance is merely a side-effect of resistance to prolonged dehydration, since the damage caused by both is very similar. Areas of low water content are common enough for this theory to be plausible, even if it is a great deal more anticlimactic than the suggestion that D. radiodurans arrived to Earth on a meteorite.
More importantly, extracts of D. radiodurans antioxidant complexes could be used to protect the antigens of bacteria and viruses when exposing them to radiation. The production of radiation-inactivated pathogens with their antigens perfectly preserved would provide us with potent vaccines.
But as interesting as this blue sky research is, does our knowledge of Deinococcus radiodurans help us? Extremophiles have been plundered for biochemical treasures before, notably Thermus aquaticus, the source of Taq polymerase, a heat-resistant enzyme used for the polymerase chain reaction which revolutionised the field of genetics. D. radiodurans could prove just as useful. In 2003, American scientists showed that D. radiodurans could be used to store information that could survive a nuclear war. They translated the song ‘It’s a Small World’ into DNA segments, and inserted this translation into the D. radiodurans genome. 100 bacterial generations later they could
“D. radiodurans could be used to store information that could survive a nuclear war” Genetically engineered strains of D. radiodurans have already been put into action, digesting solvents and heavy metals in radioactive waste. This was simply a matter of cloning the appropriate genes into the D. radiodurans genome. Alternatively, enabling other bacterial species to produce manganese-peptide antioxidant complexes could allow the use of more commonly used species to digest waste in radioactive sites. Deinococcus radiodurans may not be able to leap tall buildings in a single bound, but the next time Superman faces a Kryptonitewielding foe, he knows where to find back-up.
By Jack Cooper Art by Ruby O’Grady
fast days, and nasty side-effects on fast days such as dizziness, headaches, lack of concentration, and bad breath. A recent publication by Valter Longo at the University of Southern California has suggested that intermittent fasting may actually be good for the immune system, while other studies suggest it can be good for the brain. However, most of these are short-term studies on the effects of extreme fasting in animals and using them as evidence for health benefits of these diets is therefore unwise.
ABSOLUTELY FAD-ULOUS
These are best exemplified by JJ Smith’s “The 10 Day Green Smoothie Cleanse” which was a New York Times bestseller in 2014. Like other juice ‘cleanses’, Smith claims that there are toxins in the body that need to be rigorously flushed out through a cleansing process that involves only three smoothies, snacks (mercifully), and water or detox tea every day for ten days. By ‘smoothies’ Smith is actually referring to a blended salad of arugula, beet greens, radish tops and kale.
Do quick fix diets really exist? If there’s one thing that extensive scientific research into nutrition has found it’s that healthy eating is not difficult. In fact, the general principles of how to eat healthily are essentially captured by the food pyramids taught in primary school. Despite this, in our fairly sedentary culture saturated with high sugar diets, obesity has become a major health issue. This, combined with media pressure to look skinnier than ever, has led to a nationwide obsession with weight loss.
“these diets can leave out crucial nutrients, leading to depressed metabolism and serious health risks” Fad diets are everywhere, endorsed by beautiful celebrities with promises of achieving your dream body with minimal time and effort. However, at their worst these diets can leave out crucial nutrients, leading to depressed metabolism and serious health risks if followed for an extended period of time.
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Low-carb Diets.
Popularised by the famous Atkins diet, these diets play on the public understanding that we use carbohydrates for energy and so cutting them out completely forces the body to ‘burn the fat first’, leading to quick and easy weight loss.
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However, most of the early weight lost on Atkins or other low-carbohydrate diets is in fact caused by the loss of water tied to carbohydrate stores such as glycogen. Losing these fluid stores can lead to low blood pressure and a few days of irritability, headaches, nausea, and low-energy. Worst of all, any moderate ‘cheat-meal’ will put all that water-weight straight back on. If you do manage to survive the trauma of the glycogen-burning period without giving up and making a bacon sandwich, you enter the promised ‘fat burning’ stage, otherwise known as ketosis, which usually only occurs in starvation. Over prolonged periods of time highprotein, low-carb diets can have several
3. Juice and Smoothie Cleanses
unpleasant side effects. Note that while carbohydrate stores can be viewed by some diets as a mere barrier to fat-burning, they are actually essential for physical exertion. While tricking your body into thinking it’s starving to get it to burn fat may lead to dramatic weight loss—even if this is mostly water—this is often accompanied by exhaustion, a depressed metabolism, bad breath, and potentially kidney stones.
2. Intermittent Fasting Diets The infamous 5:2 diet: why eat every day when you can (just about) get by only eating some days? These diets often lead to unhealthy binge eating on non-
The main issue with ‘detoxing’ is the implicit idea that your liver and kidneys need help to get rid of potentially damaging molecules. Although people do vary in their ability to detoxify, and this ability is influenced by diet, boosting your detoxification pathways actually involves carefully adjusting your diet by removing potentially problematic items such as processed food, gluten, dairy, or red meat. Ironically, there is evidence that fasting detoxes such as these cleanses can actually suppress detoxification pathways in the body.
4.
The Paleo Diet
This diet represents an attempt to go back to a supposedly ‘healthier’ time when Stone Age men hunted animals while women gathered nuts and berries, both attaining near physical perfection due to their ‘natural’ diet. As well as excluding modern processed foods, Paleo diets ban anything that would not have been eaten by humans before the transition to agricultural lifestyles, including all dairy and cereal products. Success stories on the Paleo diet website include weight loss, alleviating symptoms of multiple sclerosis, and one lucky man who found that it stopped his excessive production of ear wax.This diet deserves special scrutiny from the scientific community as it claims to be founded on solid evolutionary principles. While the world we live in has changed dramatically since Palaeolithic times, proponents claim that our genome has not, and therefore we are best suited to Palaeolithic conditions. Unsurprisingly, this logic has many flaws. The idea that the human genome isn’t capable of rapid evolution to keep up with changing diets is at odds with evidence
such as the development of lactose tolerance in dairy eating populations in only 7000 years. Even more unrealistic is the assumption that our gut bacteria (crucial to digestion) haven’t changed significantly since the Stone Age. Indeed, it is actually impossible to recreate a Palaeolithic diet as the plants and animals that exist today tend to be wildly different from their ancestors due to intense natural and artificial selection. The idea that Stone Age men and women (who rarely lived to 40) should be a health inspiration ignores much of the evidence we have about Stone Age lifestyles. A recent study published in the Lancet by Professor Randall C Thompson and others found signs of atherosclerosis (arteries clogged with cholesterol and fat) in 47 of 137 mummies from four ancient civilizations across the world. Crucially, the idea that there was one Palaeolithic diet ignores the adaptability that made humans such a success in the first place.
If the logic behind these diets is so tenuous, why do they have so many die-hard fans? In general, the reason most fad diets have any success at all is because they often overlap with traditional, ‘boring’ weight-loss advice like reducing caloric intake and levels of saturated fat and exercising more. Rogue ‘expert’ scientists lend validity to the science behind fad diets, which goes unquestioned due to a lack of public understanding about the experimental rigour needed to prove the health benefits of a diet. Experiments supposedly demonstrating the power of a fad diet often have small sample sizes and lack control groups, making it difficult to assess the biological relevance of statistically significant results. But for many, dieting is not simply about
reaching a healthy weight, but is instead a reaction to constant media pressure to lose weight. Both men and women are portrayed unrealistically in the media and this has a clear impact on how people see their own bodies. The media’s obsession with female thinness has led to high proportions of healthy women feeling that they are too fat and hating their bodies. The link between media portrayal of women and plummeting self-esteem was demonstrated powerfully by a study conducted on the island of Fiji by Dr Anne E. Becker. It was found that before the introduction of television in 1995 very few girls dieted, but by 1998 69% of girls on the island had been on a diet. This increase in dieting was coupled with a 12% increase in eating disorders over the same three year period. This is the mentality that fad diets are exploiting. They promise quick and life-changing results to a population that has been fed images of unrealistic body standards and the narrative that eating healthily is painful and difficult. Perhaps this explains why, after a week of drinking blended radish tops, people don’t see that a gym membership and eating more vegetables might be easier. Or that they might not have needed to lose weight in the first place.
By Emilie Finch Art by John Molesworth
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Herbal Remedies Exposé
viral vectored vaccines Using the body’s response to viral infection to our advantage
Ancient truths Home remedies and old wives’ tales endure in the modern world. Take the ancient Chinese art of ‘cupping’ and the media storm surrounding its use by Olympians at Rio, as well as the persistence of acupuncture, homeopathy, herbal remedies, and chicken soup for colds. Clinical testing usually shows that these remedies are no better than a placebo, but from time to time we discover that there is some truth in an ancient remedy, that it has endured through generations because it provides noticeable benefit caused by active ingredients rather than by chance or the placebo effect. And sometimes these ingredients, or their derivatives, find
their
way
into
modern
medicine.
Spider silk
Willow bark
The fine filaments of protein produced from spiders’ spinnerets have received a lot of attention from the scientific community for the unusual combination of supreme mechanical and biological properties. Stronger than steel, a net made with 1cm-thick strands of spider silk could halt the flight of a passenger plane, and yet it is also extraordinarily elastic. Its proteinous structure is similar to collagen (which makes up human bone, tendons and ligaments), meaning it is largely biocompatible, and spider silk has also been shown to be antimicrobial. The ancient Greeks used spider silk to staunch wounds and today spider silk looks set to reappear on the medical scene in the form of sutures, skin graft supports, medical meshes, and dressings. There is even the possibility of using the silk to manufacture artificial tendons and ligaments, structures that must be able to flex freely and never snap despite constant flexing and applied pressure. The main barrier to the use of spider silk is the difficulties associated with its production on a large scale: spiders cannot be farmed since they become cannibalistic, and the large size of the proteins makes harvesting from genetic modified bacteria challenging.
The biologically active molecule of aspirin is salicylic acid which is formed in the stomach, liver, and blood after ingestion of the synthetic derivative found in the pill itself. Salicylic acid is also produced after ingesting salicin, a molecule present in the bark of some trees (notably willows) and other plant matter. Use of willow bark for pain relief dates back to 2000BC, and Hippocrates extolled it as a means of reducing fever and inflammation in approximately 400BC. Aspirin itself was developed as a means of delivering salicylic acid to the body in an inactive, acetylated form to avoid the nausea, vomiting and ulceration associated with swallowing pure salicylic acid.
Honey
Normally noted for their deadly toxicity, William Withering is credited with the discovery that foxgloves could be used to treat the swelling associated with heart failure (known as ‘dropsy’) in 1775. After noting its presence in a wise woman’s remedies, he meticulously studied dosage, action, and prescription methods, and published his findings in Account of the Foxglove. The active chemical was later identified and given the name digitalis, after the foxglove’s genus, Digitalis spp. A dosage almost identical to that originally prescribed by Withering is now used in the prescription drug digoxin to treat heart failure and atrial fibrillation. In excess, digitalis— in both foxgloves and digoxin— causes irregular heart rhythm, cardiac arrest, and death.
The first recorded use of honey to treat wounds appears on 4000-year old Sumerian clay tablets. Even Aristotle wrote of its virtues. has been implicated in honey’s wound-healing properties, as well ash (dehydrating bacteria via osmosis).However, it is Manuka honey, a relatively new form resulting from the introduction of European bees to New Zealand and Australia, that some researchers are now particularly focussing on. It has been shown to act against common bacteria like E. coli as well as against antibiotic-resistant strains such as MRSA. However, there remains extensive research to be carried out before Manuka honey—or any component—can live up to the rigorous drug standards that the medical industry relies on.
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Most vaccines use an attenuated or dead pathogen—viruses, bacteria or protozoa. The pathogens are detected extracellularly by B-cells. Each B-cell produces antibodies which bind specifically to different 3D ‘epitopes’ on proteins. When B-cells bind their specific epitope,in this case the surface antigen on the pathogen,they become active, start to clone themselves, and secrete antibodies which bind and inactivate pathogens. As the immune response finishes, a small colony of memory B-cells are produced which rapidly respond to future infections by the same pathogen.
“viral recombination was shown to cause cancers” But the adaptive immune system has a second set of components, the T-cells, which act to scan the intracellular environment of a cell and detect pathogens inside cells.
viruses replicate in the host and eventually cause cell death, releasing viral particles to infect surrounding cells. The infection then proceeds until the immune system can stop the virus by supressing infection though non-specific interferons before T-cells in the adaptive immune system can kill infected cells and prevent the spread. Unfortunately, during early development of vaccines a correlation was found between the replicative capacity of the virus and the ability for the virus to generate an immune response. The second risk with viruses is recombination. Double stranded DNA from any source, either viral or human, can be recombined by DNA repair, and if the virus is a retrovirus it will require integration into the host genome for its life cycle. Recombination is dangerous as it can insert into the coding region of genes and change the way the genes are transcribed. Furthermore, viral recombination was shown to cause cancers in early iterations of gene therapy. VVV research has progressed in an attempt to make viruses as safe as possible and has now reached a point where the viruses produced are efficiently able to generate a strong
immune response. The trade-off is that large amounts of virus must be used, potentially in multiple doses to get a full immunisation.
“they help us respond to emerging pathogens such as Ebola” The Jenner Institute in Oxford is one of the world’s leading vaccinology labs, particularly in VVVs, with over 50 different vaccines either produced or in development. Some of the only licenced VVVs for human use come from the Jenner Institute. Many, including Ebola vaccine in development, use replication-deficient adenovirus. This is a large dsDNA virus that infects a wide range of cell types in humans, as well as strongly activating the innate immunity through acting as an adjuvant, enhancing the body’s anti-antigenic response in a similar way to alum in conventional vaccinations. As such, VVVs sit at the front line of vaccine research in Oxford, helping us respond to emerging pathogens such as Ebola, or to well-known threats such as influenza and chickenpox.
When pathogens infect a cell they replicate and produce new, foreign proteins and DNA. These proteins can be degraded, along with the cell’s self-proteins, by the proteasome, into peptides of 9 to11 amino acids in length. These peptides are loaded into proteins found on most cells in the body (MHC Class I proteins) which present the peptides on the cell’s surface. Some T cells have a unique T-cell receptor, formed by recombination, which recognises a specific foreign peptide presented by MHC class I. Once the foreign peptides are recognised, these T-cells can release cytotoxic chemicals which kill the infected cell and prevent further pathogenic replication.
“honey acts against antibiotic-resistant strains such as MRSA” Foxgloves
Viruses can be responsible for terrifying pandemics. However, now they are offering use in a new context to tackle global health problems in the form of viral vectored vaccines.
Recombinant VVVs use both of these systems, activating both B-cells in extracellular fluid and T-cells through infection. The VVV genome has been engineered to contain short DNA segments which code for short peptides that are found in the proteins of pathogens. The T-cells then recognise this peptide bound to MHC on the cell surface and initiate an immune response, resulting in a colony of memory cells specific to this peptide which can quickly become active in subsequent infection.
By Josephine Pepper Art by Gulnar Mimaroglu
VVVs were first theorised in the 1970s but their associated risks hindered their application. Most viruses are pathogenic, killing or damaging the host cell. The
by Ciaran Gilbride Art by Sophia Malandraki-Miller
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Bang! Talks to…
ADRIAN HILL
And how did you become involved with the Ebola vaccine? It was early August and the WHO and the Wellcome trust both had the same question for me: how quickly can you do a clinical trial? Of course the answer is that it depends on whether you have a vaccine or not. So what we really did with Ebola was take several vaccines into clinical trials very quickly. We were very lucky that the vaccines existed at all; they were being manufactured in lots of doses by American scientists at the NIH and in Canada, who were preparing vaccines to protect North Americans against a potential bioterrorist attack, funded by biodefense money. These Ebola vaccines had been tested in animals (quite well actually). The vaccine was a chimpanzee adenovirus but with some of the key genes in that adenovirus taken out so it doesn’t replicate in the body, and, more importantly, with other genes from Ebola put in. The results were being published and they looked very good. With a single dose of vaccine you could get complete protection in a small number of monkeys that lasted for weeks and months, but it was much less than a year. And all of those vaccines were being given to people for the first time so we didn’t know if they were safe, we didn’t know whether they would produce an immune response, and we certainly didn’t know whether the immune response would be enough to make a vaccine work. So we set out to do [human] clinical trials as quickly as possible. Not just in Oxford, but moving to West Africa as soon as we could. (Of course, because the outbreak was in West Africa, the WHO wanted safety data in West Africa rather than in healthy Oxford young people.) We managed to start in Oxford on the 17th September and in Mali in West Africa in the first week of October.
spider silk has also been shown to be antimicrobial
“That’s less than a year and a typical vaccine takes about ten years” In early 2015 the Ebola virus was virtually unknown to the minds of most, but by August of that year it had begun to dominate the world’s media. By October it was of primary concern to the scientific minds of the Jenner Institute, most notably the mind of its Director, Professor Adrian Hill. Hill, a graduate of Magdalen College, Oxford, joined the then newly established Weatherall Institute of Molecular Medicine as a Wellcome Senior Fellow in 1988 and now works on behalf of the Jenner Institute in partnership with Oxford University to help respond to human and livestock outbreaks by developing vaccines against various pathogens, ranging from TB to HIV. Professor Hill’s malarial research was temporarily halted when demand for an Ebola vaccine, following the epidemic in West Africa, called for an immediate change in research priorities. It
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was Hill’s team which led the way in vaccine trials. The man himself spoke with Bang!
How did you first become interested in vaccine development? I wasn’t trying to do vaccine development! I did my degree in medicine here in Oxford then did a DPhil on thalassemia and haemoglobin disorders. I got interested in selection by infectious diseases and then in selection in human leukocyte antigen (HLA) genes, working on this in Uganda. This was really eye-opening, especially as I had never worked in Africa before. It was extraordinary how bad a malaria season in Africa was—a mini epidemic for
three months every year. Hospital wards would fill up with two or three kids per bed. One million children per year were dying of malaria back in 2000. There are a variety of ways of controlling malaria such as bed nets and spraying and we are now down to around 500,000 deaths. But it was clear to everyone if there was a vaccine you would be able to reduce childhood mortality by quite a lot. I became interested in that. So I guess it was the combination of doing immunology, genetics on malaria, a lot of fieldwork, and being in a really good immunology lab.
To do a clinical trial you need a regulator—in the UK that’s the MHRA, the Medicines and Healthcare products Regulatory Authority. You need an ethical committee to approve it. You need the vaccine released to trial. We managed to get approval very quickly because we have a manufacturing facility onsite and were using [the same] type of vaccine for TB and HIV. It was great because everyone was interested and volunteered at a rate we had never seen before. We had enough volunteers for the trial before we were even officially advertising for volunteers for the trial. That will probably never happen again. But it really helped us recruit quickly because it was unclear whether the vaccine worked well enough and we had to make a second viral vector vaccine called MVA, and measure
the immune responses with that (which were clearly very strong). Luckily the volunteers were great and were willing to come back so we ended up testing several different vaccines and several different regimes and doses to try and get the ideal dose to use in West Africa. In total, of the five vaccines that were used in West Africa during the outbreak, four of those were tested in Oxford. Two of those were done by our group here at the Jenner Institute and two were done by the paediatrics group who share the same clinical centre as us in Oxford. In the end lots of vaccines went into initial testing in West Africa but only one of them got all the way to testing for efficacy, and that was 100% effective. It was published by July. So we had a vaccine going into the first human being in late 2014 and the phase three efficacy trial result being published in summer of 2015. That’s less than a year and a typical vaccine probably takes about ten years. Everything was hugely compressed. People ask if we can do that every time [we need a new vaccine] and the answer is no because we jumped the queue. The ethical committee meets every month so we have to apply a month in advance. When we applied in August they said there was a problem because the September meeting wasn’t happening; there was a training day instead. But we explained and they met specifically for our trial and approved it the same day. Also, it takes 30 to 40 people to produce a vaccine. The manufacturing people, the doctors and nurses, the regulatory people— you just can’t create that team in months, even with all the money in the world unless the whole team is assembled for something else. The something else in our case was the malaria vaccine. We did delay our malaria trial to do Ebola. The longer term effects have been arguably more important. It was exhilarating, it was remarkable
and it’s an example of what you can do if everyone wants to do clinical trials quickly.
There was a lot of media attention surrounding the Ebola epidemic in West Africa. Do you think this was beneficial to your research? There are pros and cons, but the pros were faster recruitment and much needed public awareness of how important Ebola is. The journalism was pretty good actually—it wasn’t too sensationalist. A lot of people were very interested in the science. Now we need stockpiles of vaccines. The good news is three big companies all have Ebola vaccines. None of them are strictly licensed yet but they are available for use and they all almost certainly work well. The bad news is that there are two strains of Ebola, the Zaire strain that caused the outbreak in West Africa and a Sudan strain that nobody made a vaccine for. People are working on it, but it hasn’t happened yet. And worse than that, there are about 12 outbreak pathogens that we don’t yet have vaccines for that can cause outbreaks, have caused outbreaks and will cause outbreaks but that there’s no business case to make a vaccine for, for example Rift Valley Fever. As with Ebola, we never know when there is going to be a big outbreak.
Could you explain how the Ebola vaccine works? It works in quite a traditional way. Most vaccines work by using antibodies. What we do is take the antigen and
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clone it into a DNA based viral vector known as an adenovirus. It is not dangerous as it is missing key genes which are replaced with genes from the pathogen such as Ebola, along with a strong promoter. The immune response is very good with just one dose of the vaccine. This was very useful in the Ebola outbreak since with multiple doses there can be issues of people returning and timings.
What makes Ebola an ‘easy’ pathogen to develop a vaccine for? We can identify the key antigen to put in a vaccine more easily than in other pathogens such as malaria. To give a scale, the malaria pathogen has 5,000 genes. We have been working for 20 years and have four or five but are not sure whether these are the best ones, since picking four or five from 5000 takes a lot of screening. However in Ebola there are only seven, and only one which coats the [outside of the] virus. Also, even within the strain there is only a very small amount of variation and the amount of antibody needed to protect against Ebola is very little.
How has vaccine technology changed over time? The first vaccine was developed in 1796 in England by Edward Jenner using a virus from
“vaccines save around 2.5 million lives per year” a cow to vaccinate against smallpox. 100 years later microbes were discovered and 20 years after that so were viruses. Louis Pasteur did a lot [for vaccinology] in the 19th century by isolating the virus, killing it, and vaccinating people. Of course he didn’t know anything about of viruses or even DNA at that time. But often it wasn’t great for people; there were many side effects! Until around 1950 we only used full viruses either attenuated (inactivated) or killed, like Pasteur did. When HIV came along methods like this didn’t wouldn’t work so we had to go to molecular level. Now lots of modern vaccines use genetic engineering such as protein expression or subunit vaccines. There were about eight different Ebola vaccines developed and all of these techniques were new in the sense that no existing vaccine uses that technology they had. The technology is getting much better.
vaccine for babies is for Respiratory Syncytial Virus (RSV). We also now have vaccines for teenagers against cervical cancer and for the elderly to prevent flu. In the developing world the situation is very different. We don’t have a good malaria or TB vaccine.
And so what is next big pathogen which requires a vaccine? There are many problematic known pathogens. But there are always newly emerging ones such as SARS (Severe Acute Respiratory Syndrome) which there are no vaccines for. This is not because nobody has tried! Take SARS as an example. Lots of people tried to develop a vaccine but the outbreak was controlled in weeks so they all stopped! So there is a major issue with unknown pathogens.
What is the next challenge in vaccine development? Historically the main challenge has been vaccines for children. We now have wonderful system in place—over 90% of babies born over the world every day have around ten vaccines which saves around 2.5 million lives per year. The only missing
Pain Prevention Learning from some Remarkable Rodents
By Vicky Pike and Jess Gorrill
Naked mole rats aren’t much to look at, but it’s unlikely you’ll have the chance since they live in underground colonies in East Africa. Yet what they lack in looks is made up for in other attributes as a result of their unusual, subterranean lifestyle: a resistance to cancer, surprising longevity and apparent insensitivity to pain. The latter has led many scientists to investigate their physiology in the hope of discovering new methods of treating or preventing pain in humans. Scientists based in Germany have recently made significant progress in understanding what gives naked mole rats such an incredible pain threshold, which seems to boil down to the inefficiency of certain pain receptors. Damir Omerbăsić and colleagues focused their studies on these rats’ immunity to inflammation. When other mammals injure themselves, the injured part of the body can become inflamed, becoming sensitive to touch and temperature changes. This hypersensitivity in response to inflammation, known as ‘hyperalgesia’, is completely absent in naked mole rats. In humans and other rodents, hyperalgesia is
“naked mole rats have a resistance to cancer, surprising longevity and apparent insensitivity to pain”
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regulated by a compound called nerve growth factor (NGF) which binds to specialised receptors on nerve cells and subsequently triggers a series of reactions that cause inflammation and hypersensitivity. NGF
and its associated pathways have been the focus of pain treatments before: antibodies that bind to NGF, thereby preventing it from reaching any NGF receptors, have been proven to treat pain. However, there are concerns about unintended side effects. As a result, there are calls for alternative, more focused treatments. Omerbăsić and his team started by making recordings from both mouse and naked mole rat sensory neurons essential for inflammation in response to NGF. These confirmed that, while NGF sensitised certain positively charged ion channels (TRPV1 ion channels) in mouse cell membranes, it had no effect in naked mole rats. Naked mole rats aren’t just gritting their teeth and bearing the pain, they genuinely aren’t feeling it. Interestingly, genetically modified mouse cells with the naked mole rat version of the TRPV1 ion channels were still able to be sensitised as normal. This implies that the TRPV1 ion channel isn’t the source of the naked mole rat’s pain immunity, and
that it must be some component further upstream in the NGF signalling pathway. The next crucial experiment focused on the receptor that detects NGF in the first place: a protein known as TrkA. The authors found that cells expressing naked mole rat TrkA receptors showed much less TRPV1 activity compared to those expressing a normal lab rat version of TrkA. This reduced activity showed that a small change in the genetic code of a naked mole rat compared to other mammals is sufficient to prevent NGF from initiating an inflammatory response. The results of Omerbăsić et al’s investigation have highlighted a new target for pain-related treatments in humans. Changes to the TrkA receptor are clearly sufficient to prevent inflammation and the associated pain in naked mole rats, which implies that efforts to develop drugs that target this receptor in humans could prove fruitful. By targeting the receptor that detects NGF, this treatment could reduce the need to target NGF itself, leaving the compound free to effect the rest of the body as it normally would do, thereby reducing side effects. TrkA also performs roles other than mediating inflammation, however, so it is possible that targeting this receptor could cause other side effects. Time will tell whether these will be mild enough to justify TrkA inhibitors as a pain-relief treatment.
by Johnny Page Art by Ruby O’Grady
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Calling time on the obesity epidemic Adjusting body clocks may alter fat metabolism
have gone through targeted modification which often aims to enhance specificity.”.
“Much like the action of selecting the correct gear when driving, the drug promoted more vigorous energy expenditure” However, Dr. Cheng is optimistic that his drug uniquely hits the clock with the right amount of force not to disrupt its balance and is potent enough to be used in low concentrations.
We all have those friends who can chow down a Christmas lunch without seeming to gain an inch on their waistline. It may be that these lucky individuals have a stronger body ‘clock’, and studies have shown that the innate body clock can be altered. Dr Zheng Cheng and colleagues at the University of Texas have shown that a compound called Nobiletin, found naturally in citrus peel, can increase the power of the clock in mice, and that this also seems to reverse their obesity. Your body clock is the internal timing mechanism in all body cells that ensures that all the chemical reactions in cells, and therefore bodily functions, are optimally tuned to a 24-hour day. Its ‘cogs’ are proteins that are made and degraded in response to light over a 24-hour cycle. These proteins in turn activate other genes to cause the daily routines in cell physiology known as circadian rhythms. Your clock is tightly coupled to your metabolism, and the two systems interact reciprocally; the genes involved in metabolism produce chemicals that regulate the clock, while the clock’s response to daylight ensures that metabolic pathways are active at the correct time.
Dr Cheng and his team seem to have hit gold. Nobiletin increases energy expenditure and seems to cause weight to simply melt away. Treatment of obese mice with Nobiletin caused a 40% weight decrease without any decrease in food intake, and a significant proportion of the loss was body fat. Further analyses showed normalised levels of cholesterol, insulin and glucose levels in the mice post treatment. (Abnormal levels of these substances are associated with obesity related disorders in humans such as heart disease and type 2 diabetes.) The weight loss is hypothesised to be due to increased energy expenditure during physical activity—treated mice ran longer on wheels and consumed oxygen more rapidly. Much like the action of selecting the correct gear when driving, the drug promoted more vigorous energy expenditure. To investigate whether these protective metabolic effects were acting on the circadian clock, the drug was also given to mutant mice with a faulty clock. Weight loss was not observed in these mice, confirming the necessary role of the clock in the drug’s mechanism.
“all the chemical reactions in cells, and therefore bodily functions, are optimally tuned to a 24-hour day”
For Nobiletin to be an effective treatment it must be non-toxic and without side effects, a combi-nation rarely achieved by drugs against the clock. Toxic high doses are needed and side effects are probable because the clock balances many processes. For these reasons most other drugs against components of the clock will not be approved for treatment.
Evidence linking the clock to metabolism is well established. Studies have indicated that shift workers are at higher risk of obesity, and genetically modified mice with altered clock genes show various metabolic abnormalities. Excitingly, the proteins of the clock have been well characterised and can be targeted by drugs, so obesity treatment via the clock may become a promising new therapeutic avenue.
Similar apprehensions were shown regarding Nobiletin, mainly because it was a small molecule which “tended to have more than one molecular target, hence having side effects of varying degrees.”, according to Dr Cheng. Furthermore, Nobiletin was identified by a process called screening, in which it was chosen from a large library of compounds. Side effects are more likely for a “screen-identified compound such as Nobiletin compared with ones that
Doctors won’t be prescribing a citrus peel diet any time soon but, if successful in humans, Nobiletin would fulfil an as-yet unmet demand for anti-obesity drugs.
by Sophie Catchpole Art by Ruby O’Grady
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Bang! Talks to… John Parrington John Parrington is a Professor of Pharmacology at the University of Oxford and author of the new book ‘Redesigning Life – How genome editing will transform the world’ which is out now.
a mutation that occurs in a wild potato species in South America and they’ve introduced this into commercial potato strains to make them resistant to blight.
Do we have enough knowledge to be playing around with complex organisms and ecosystems on such a fundamental level or is more research needed?
In the past we were adding a foreign gene that would insert itself randomly into the genome; there was no control. With the new technique there is less chance of unintended consequences on the genome but obviously if you change any organism in the wild you’ve got to be cautious. Altering a field of potatoes seems very innocuous, but is there a possibility of gene transfer spread to other species in the wild? I don’t see there being an obvious major risk as these are not foreign genes—we are just changing a commercial species to be ever so slightly different. When it comes to modifying pathogenic species like mosquitos there’s a version of genome editing called mutation chain reaction. A genetic change will spread across a population. Some people think that would be great; we could make mosquitos unable to carry malaria or turn them all female to eradicate a population. However, you don’t really know what the long term consequences might be or the effects on the ecosystem. Many scientists are wary of the potential ways this might all go wrong and we need a proper debate.
Tell us about the basics of genome editing. How does it work?
What are the benefits of being able to modify the genome with such precision?
Essentially, it is the ability to cut and paste in the living cell. In the past, scientists could cut and paste DNA in a test tube using specific enzymes. You could chop out a gene from the human genome and paste it into a vector [a carrier DNA molecule]. This led to us being able to produce human insulin for the first time.
One of the benefits is to be able to make better animal models of disease. We can make very precise ‘knock out’ or ‘knock in’ models in mammals [deliberately activating or deactivating an existing gene] to better understand how our own mammalian bodies work. We can do this in anything from a pig to a rabbit to a monkey. This could be very important for studying how the brain works. For example, monkeys have a prefrontal cortex which is a part of the brain involved in human cognitive functions. This could allow modelling of diseases such as schizophrenia and bipolar disorder.
However, we lacked an ability to precisely modify the genome—a way of cutting DNA in a living cell in a specific part of the genome without killing the cell in the process. The major new discovery is of a system in bacteria called CRISPR-Cas9. Bacteria use this to defend against viruses. You can commandeer this system and reprogram CRISPR-Cas9 in a test tube to target any genome of any species in a living cell at any point in the genome. That is the basis for a genetic revolution.
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I think the other major areas that will benefit are agriculture and medicine. We’ve had a dream of personalised gene therapy for a long while, of being able to treat cystic fibrosis, Huntington’s, and other ‘single gene’ disorders. It seems to me we are now a lot closer to being able to treat those kind of disorders. However, the more we learn
about the genome, the more complicated it appears to be. Over 120 different parts of the genome are linked to schizophrenia, for example. So trying to treat these diseases with gene therapy could be very problematic. In agriculture, there has been a lot of controversy over genetically modified (GM) crops and the ways in which these plants are being created. Genome editing will dramatically increase the precision with which we can engineer plants and animals. One of the exciting things about the new technology is the possibility of taking a mutation that maybe occurs naturally in the wild and then introducing this into a commercial species.
“The more we learn about the genome the more complicated it appears to each” To give you an example, potato blight is a major problem. The millions of dollars spent spraying potato crops is both an economical issue and also an issue in terms of the environment. Scientists have found
palatable to people who are against GM. We are talking about improving food quality, eradicating disease, improving the welfare of the animals. We can move away from the idea that being pro-organic and pro-sustainable means you have to be anti-GM. We badly need an ethical, sustainable approach looking at the current state of the planet. I think we need dialogue really. I am always happy to debate with opponents of genetic engineering to put my side of the story across.
You have written a lot of popular science in publications such as The Guardian. Do you think the scientific community needs to do more to communicate science breakthroughs like genome editing to the public? There is a lot of popular science around, lots of it written by non-scientists. Some scientists think popular science is a waste of time and not all scientists are good communicators. I don’t think it should be a requirement, but personally I think it makes a difference to have working scientists popularising science. Ultimately, we are funded by the public and something as big as genome editing is going to transform society. I really believe [genome editing] will have a massive impact, and people ought to know about this.
How did you become interested in writing popular science? Do you have any advice on communicating science? When I was in school I really enjoyed English Language and Literature. At my school we were forced to choose between science and the arts, but I came back to this love of literature and writing later on. I particularly think it was doing a British Science Association Media Fellowship with The Times which was a catalyst. I was writing about all different aspects of science and I really enjoyed it, but I wanted to carry on being a scientist. At that point, book writing seemed to be the way to go.
“We need dialogue. I am always happy to debate with opponents” I also did courses in science communication and creative writing. They were part time so I could carry on with my job as a scientist and lecturer. I recommend taking a course like that, as well as writing science for a magazine or local newspaper. Pitch ideas to editors; they may be interested in a piece about the research that you are involved in. The first piece I wrote in a national newspaper was about my own work on fertilisation. You can provide a personal take on the story.
by Daniel de Wijze
There has been a lot of public backlash towards GM crops. Do you think there will be a similar response to genome editing? A lot depends upon looking at what has been proposed, what the change is, who is doing it, and for what motives. I recently had a chat with a company who are trying to develop sustainable, ethical methods of agriculture, in the possibility of using genome editing to improve animal welfare. There are adverse effects to conventional breeding methods, such as chickens bred to grow as fast as possible, so fast that their skeletons are very weak. We could reverse some of those changes by genome editing. We could prevent tail docking in sheep, which is a painful procedure but carried out because long tails can favour infections like fly strike, if we breed sheep with shorter tails. If you can market this technology as something that could benefit cattle and pigs and sheep maybe it would be more
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iGEM searches for a
re
Wilson’s Disease: Cutting Down on Copper
This summer I am working on the Oxford team in the iGEM competition to create copper-chelating E. coli that could be used as a treatment for Wilson’s disease. This is the third year that the university has entered a team for the international Genetically Engineered Machine competition, in which interdisciplinary teams of students in universities and schools around the world use synthetic biology to solve real world problems. Within the projects, DNA sections with known functions called BioBricks can be ordered from a registry of standard parts or created by teams and then fitted together in the bacteria to make them perform a certain task. The aim of iGEM is not only to make scientific advances but to encourage collaboration between teams and engagement with the public. Wilson’s disease is a rare genetic condition affecting 1 in 30 000 people which causes the body to retain too much copper. Our diet contains more copper than we need and normally the excess is removed from the liver by a carrier protein, putting it into bile for excretion. However, in Wilson’s disease a genetic mutation means that this carrier does function correctly. Copper remains in the body, accumulating mainly in the liver and brain. This can cause liver damage and neurological symptoms such as balance disturbances and slurred speech. If left untreated, Wilson’s disease can be fatal.
Currently Wilson’s is treated with copper chelating drugs, either Penicillamine or Trientine, which bind to copper in the small intestine before it can be absorbed. These have to be taken before every meal of the patient’s life and can have toxic side effects. Patients must avoid foods that are high in copper such as chocolate and seafood. Furthermore, the small patient numbers mean drug companies charge very high prices for their products, making it difficult for patients to obtain their medication.
“The aim of iGEM is to encourage collaboration between teams and engagement with the public” Oxford iGEM’s solution is to introduce our probiotic bacteria into the small intestine to create a stable population that will chelate copper before it is absorbed. This is how the current drugs operate but since the bacteria would be self-renewing the drugs would not have to be taken every day and there would be no risk of a patient forgetting to take their medication. In theory this would be cheaper than the current drugs, there would not be the toxic side effects and there would be no need to restrict the amount of copper consumed in the diet.
“it would be cheaper than the current drugs and lack the toxic side effects” The E. coli will produce a newly discovered copper chelator protein from a distantly related bacterial species which would be controlled by a copper sensitive promoter system native to E. coli. This system activates the genes used to make the chelator when copper is sensed so that when the free copper concentration in the intestine is high the bacteria can produce the chelator and store the copper itself before it can be absorbed by the small intestine. When the copper concentration is low the bacteria will not produce the chelator, conserving its own resources and saving the patient from copper deficiency. Due to time constraints and the need for rigorous safety testing this project will only be a proof of concept rather than an actual treatment. However, we believe that probiotic treatments such as ours will be more widely used in the future as a long term solution to many chronic health problems.
by Rosie Brady
The Chicken and The Egg: A study of embryonic development “Lectures stop you from seeing development for the storm of cells it truly is” This summer I worked with the Kulesa lab at the Stowers Institute for Medical Research in Kansas City, helping them in their efforts to understand neural crest cell migration. I willingly concede that studying embryonic development at university can be rather dry. Many lectures simply take the form ‘X turns into Y, and then Y turns into Z’, an endless sequence of slides depicting precise stages of growth. Learning about development in this way forces you to conceptualise the embryo in a similar manner to trying to understand a video by studying single frames. It stops you from seeing development for what it truly is—a storm of cells. To take a single fertilised egg and turn it into an organism with distinct structures and a pantheon of cell types, embryonic cells must undergo rounds of proliferation, division, and differentiation. In other words, they must produce the raw materials and mould them to purpose. The development of many tissues depends on cell migration, a process in which the right cells need to travel to the right destinations. There are many ways in which cell migration could go wrong and, when it does, developmental disorders result. To deepen our understanding of cell migration and work towards the prevention of birth defects many scientists study neural crest cells. Neural crest cells are found in the early vertebrate embryo and are notably multipotent, contributing to structures as disparate as sensory neurons, veins, and pigment cells in skin. This means that there is great motivation behind the attempts to understand their migration, since there are a great deal of disorders that have neural crest cells at their root. The behaviour of migrating neural crest cells also makes them an ideal experimental model since they migrate in cohesive streams that are highly stereotypical between different embryos. This means that the cells are easy to locate and abnormal migration is easy to spot, a fact which is particularly helpful for summer interns! The Kulesa lab studies neural crest cells in chick embryos since they are easily obtained and accessed from eggs. Their previous work has shown that there are at least three distinct
neural crest cell sub-populations at different positions along the migrating streams, differing in their molecular profile and behaviour. A number of genes that may be differentially expressed across the sub-populations have been identified. My project systematically investigated the expression of 12 such genes in order to determine whether or not they were differentially expressed. I used the new fluorescent in-situ hybridisation technology RNAscope, which has the advantages over other in-situ hybridisation technologies of having lower background noise and higher resolution. This labels the mRNA products of these genes with fluorescence, allowing them to be seen under a microscope. Indeed, I was the first to systematically investigate gene expression in chicks with RNAscope. The protocol began with harvesting embryos from fertilised eggs and dissecting relevant tissue using incredibly thin wire. Performing microsurgery on an ordinary chicken’s egg is a very strange experience! The embryos were then cleaned, fixed, and treated with RNAscope reagents in order to preserve and label the mRNA transcripts that indicate levels of gene expression. RNAscope reagents build up protein scaffolds on transcripts of interest, onto which fluorophores—fluorescent dyes—bind. Immunohistochemistry was then used to mark the neural crest cells themselves, to make sure that the right cells were being identified under the microscope. After putting the embryos through tissue clearing to make them almost transparent, I mounted them onto microscope slides so that I could finally see the fruits of my labour. Opportunities such as the Stowers Summer Scholars Program are invaluable. They give students the chance to perform world-class research at a world-class facility with a degree of independence that most will have never experienced before. It’s great to know that my research will inform future work in the Kulesa lab and could ultimately be used to better understand embryonic development.
“my research will inform future work”
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by Jack Cooper Art by Ruby O’Grady
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BOOK REVIEWS:
Zoe Catchpole on The Emperor of All Maladies
In this monster of a book Siddhartha Mukherjee documents a lifetime of cancer research and treatment in a biography of the disease.
The style is very different to many other popular science books (it reads more like a history book than a popular science book), which took some getting used too. Mukherjee
Biography is the perfect description. Cancer is a disease of multiple faces and Mukherjee cleverly captures this by interweaving the individual histories of researchers, practitioners, and patients throughout the ages. But as a researcher and practitioner himself Mukherjee offers a unique perspective. The narrative of his own leukaemia patient, Cara, metastasises throughout the book.
“metaphors for cancer multiplied with every page”
A lot of popular science books about cancer can feel very separate from human cost but Mukherjee is able to fuse the two. Just pages after a patient loses their battle with cancer the treatment that could have saved them is discovered.
feels the need to and the number of for cancer multiplied seemed like he was for the right words to
What Does It Involve?
But despite this dense style it couldn’t be more comprehensive and was an incredibly rewarding read, certainly deserving of the Pulitzer Prize.
Training as a Patent Attorney is a career path that will enable you to combine your understanding of science with legal expertise.
Josephine Pepper on The Panic Virus
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A CAREER AS A PATENT ATTORNEY?
An intellectually challenging and rewarding career option
overuse adjectives different metaphors with every page. It constantly searching describe the disease.
You will leave the lab environment yet remain at the cutting edge of science and technology, applying your knowledge and skill in a commercial context. You will help to protect intellectual property assets and grow businesses.
The Panic Virus is a comprehensive account of the hurdles thrown in the way of public vaccination programmes throughout history, with a particular focus on the familiar autism scare (of both the MMR vaccine and thimerosal). It offers a fascinating and detailed exploration of the extent of the damage that can be caused by a handful of rogue medics, distraught parents, the internet, and a sensationalistic media.
table before guiding the reader through the scientific and political principles employed in vaccine research and court hearings, meaning any conclusions he draws relating
“A detailed exploration of the damage caused by ... sensationalistic media”
to the efficacy, safety and necessity of vaccination are rigorous and convincing. It’s imperative that books like this—with academic rigour and clarity of expression and, most importantly, backed by extensive scientific research—reach as wide a general audience as those written by the often more vocal anti-vaccine activists before public faith in vaccination is irrevocably shaken.
While Mnookin’s incredulity of the actions of Wakefield and other anti-vaccine activists is clearly explained and justified, he does not allow his convictions to cloud his lucid writing style or to prevent him from detailing instances in which government corporations such as the American CDC failed to respond effectively to public concerns over immunisation. He places all the cards on the
HAVE YOU THOUGHT ABOUT...
“the conclusions he draws are rigorous and convincing”
James Egleton MChem in Chemistry, University of Oxford (2011) DPhil in Organic Chemistry, University of Oxford (2015)
Sound Interesting? Patent and Trade Mark Attorneys in London, Oxford, Cambridge and Munich. We welcome applications from exceptional candidates at any time of the year. Eleanor Healey BA and MSci in Natural Sciences, University of Cambridge (2011) DPhil in Structural Biology, University of Oxford (2015)
www.jakemp.com/careers