Synapse Science Magazine #12 (Biomedical Issue)

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SYNAPSE THE SCIENCE MAGAZINE WRITTEN BY STUDENTS FOR STUDENTS

ISSUE 12 - January 2016

University of Bristol

Medical 3D-Printing The Mouldy Tale of Penicillin

Nanoparticles in Medicine

The Team George Thomas Editor-in-Chief

Amy Newman Vice President

Jessica Towne

Secretary & Senior Editor

Mutanu Malinda

Treasurer & Senior Editor

Gabriel Penn

Chief Graphic Designer

Melissa Levy

Managing Editor

Nina Smith

Managing Editor

Rachel Baxter Media Director

Marta Plaszczyk Senior Editor

Kieran McLaverty Senior Editor

Sophie Groenhof Senior Editor

Cover image kindly supplied by

Professor Dek Woolfson 2 | SYNAPSE

Welcome to

SYNA PSE Science Magazine

W

elcome to the 12th issue of Synapse, the University of Bristol’s science magazine written by students. This issue is biomedical themed, to celebrate the formation of the new Biomedical Sciences Faculty. Our writers have explored an exciting range of topics, from Alzheimer’s disease and the science of sleep to some of the interdisciplinary research making medical advancements, including 3D printing and even particle accelerators. We also have an exclusive interview with Dr. Paul Race from the faculty, who tells us about Bristol’s synthetic biology research centre. Be sure to check out our blog too for more articles on a wider range of topics, and remember you can get involved by joining us on the Bristol SU website.

E: synapsebristol@gmail.com

Editors

EDITORIAL

Stefan Rollnick James Portman Chelsie Bailey Aleks Marsh Abbie Wilson David Morris Akanksha Subramanian

Synapse wishes to acknowledge the support of the Biomedical Faculty of the University of Bristol.

CONTENTS

3D Printing in Medicine Could Alzheimer’s Be Infectious?

A Blood Test to Diagnose Heart Failure How Fatty Foods Can Prevent Seizures Interview: Dr Paul Race from the School of Biochemistry

4 6 8 10 12

Anti-Malarial Drugs:

15

Perkins’ Metallic Tractors:

16 18 19 20 22

Are they at risk of becoming ineffective?

The placebo effect revealed

Treating Cancer With Particle Accelerators Nanoparticles in Medicine The Mouldy Tale of Penicillin Simulated Guilt ‘Sleepy Heads’: Sleep for students

Synapse Strips

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ARTICLE

3D Printing in Medicine

I

n 1984, the first 3D printer was developed by American engineer Chuck Hull. It was designed to rapidly screen prototypes to improve job efficacy in the engineering industry. Over the past few decades, as the technology and methodology has developed, 3D printing has found uses in vastly different applications far beyond the capabilities that were originally expected.

3D printing is now heavily incorporated into the modern world. It is primarily used to generate prototypes for different kinds of motors, from motorcycles, aeroplanes and space rockets, to making models for commerce or teaching, in the production of precise electronics, and so on. As the methodology of 3D printing has developed, the range of materials and potential size of the products has also grown, hence such printed objects like bike frames, furniture, guitars and even cars have been produced. More recently, Chinese companies have even invested in the technology for modular construction of 3D printed buildings. They have been created such that they are thermally insulating, water, fire and corrosion proof, and can withstand earthquakes rating 9.0 on the Richter scale.

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The 3D printing process was originally performed by the systematic addition of layers of powdered UV-sensitive polymer.

After the addition of a layer, a mask of the desired pattern would be placed over the layer and UV light shone through it.

The exposed areas could then be washed away with acid whilst leaving the rest untouched, defining the pattern. This process was repeated with different masks until the full 3D object had been created.

Other methods were then explored and used to exploit the chemistry of different materials in order to produce the desired shape in different materials.

3D printing has now been proven to be revolutionary to not only the manufacturing industry, but also in modern medicine. Over the past year, medical miracles have been performed by the creation of organs and bones for surgical replacement. Such work was performed on a chest wall sarcoma patient after removal of the tumour necessitated the removal of his sternum and swathes of his rib cage. Due to the highly specific level of removal, it was doubtful that a donor would match the needs of the patient. However, recent investment into this area allowed for a titanium replica of the removed bones to be 3D printed by

selective fusion of fine titanium powder.

The replica was printed to astounding precision and surgically implanted, and the patient is now recovering quickly and successfully.

For nearly ten years now, the use of 3D bioprinting has been developed for the replication of organs that are 100% compatible with the patient, to negate the need for anti-rejection drugs. The process involves taking the stem cells of a patient and using 3D printing technology to create artificial organs out of those cells.

In 2013, a three month-old baby suffering from a rare condition resulting in tracheal collapse had a fully functioning 3D bioprinted trachea surgically implanted.

The implantation saved the child’s life and the trachea is fully compatible with the growth of the child. However, this method is currently limited in the tissues it can make due to the complexity of such biological systems.

Last month, the FDA approved the first 3D printed drug called Spiritam, an anti-seizure drug for epileptic patients. It is made by depositing a powdered form of the drug at specific intermolecular distances to form a very porous pill. As a result Spiritam dissolves very readily in water and is easily ingested, which can help in conditions such as epilepsy where swallowing can be difficult.

As these medical applications demonstrate, 3D printing is rapidly revolutionising biomedical science and pharmaceutical engineering. It has been postulated that issues involving the printing of cartilaginous tissues will be solved over the coming years, meaning

that soon enough more complex biological systems will be available for transplant.

Similarly, abandoned pharmaceutical candidate drugs that dissolve poorly in water can now be revisited as the porous 3D printed versions may suffer no such problem in the body. With this, it is clear that biomedical science is starting to take a tremendous jump in being able to improve the lives of people with any number of physical or mental conditions.

David Morris

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ARTICLE

Could Alzheimer’s Be

Infec tious?

Kieran McLaverty

A

lzheimer’s is one of the most devastating and poorly understood diseases of the brain.

The cause of this neurodegenerative disease is under hot debate. Leading scientists in the field believe that the problem arises from poorly folded proteins collecting en masse in the area of the brain known as the cortex.

A recent research paper from scientists at UCL has added another shocking dimension to this disease: the idea that it’s infectious, specifically through injections of contaminated hormones. Researchers have dubbed this discovery a ‘paradigm shift’ in the understanding of Alzheimer’s.

But what form would this infectious particle come in? How could a single molecule of protein replicate without the machinery afforded to other pathogens such as viruses or bacteria? The answer to these questions lies in the detail of

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another, less well-known group of pathogens: prions.

Prions are poorly folded proteins that act almost like enzymes, interacting with similar proteins and forcing them to change their structure, rendering them useless.

As the number of deadly proteins increase, so too does the rate of disease progression. The prognosis is almost always fatal.

Creuzfeldt Jakob Disease (CJD) is an example of such a disease a disease caused by prions. Like Alzheimer’s, CJD is thought to be caused by the mis-folding of proteins, giving brain tissue an abnormal ‘sponge like’ appearance when observed under a microscope. As our understanding of Azheimer’s deepens, more parallels are being drawn between Alzheimer’s and other prion diseases.

The key to understanding how prion diseases manifest requires

are poorly folded proteins that act almost “ Prions like enzymes, interacting with similar proteins and forcing them to change their structure… ”

knowledge of protein structure and folding. All known prion diseases have one structural feature in common – the amyloid fold. This fold imparts great stability on the prion and leads to decreased solubility. As a result, these proteins cluster together in structures known as aggregates.

This stability allows prions to resist vigorous disinfection and remain on surgical instruments.

The most common way of acquiring CJD and Alzheimer’s is through sporadic mutation events in your DNA. This happens through a small mutation in a gene, resulting in a change in protein structure. It is possible that people have a higher risk of developing CJD/Alzheimer’s if the allele they possess is structurally very similar to the mis-folded protein.

CJD can also be contracted through the consumption of contaminated food. An example of

this would be mad cow disease (BSE), where prions accumulate in the nervous tissue of cows, but can also be found in blood. BSE affected the UK especially badly. By 2014, up to 177 people had died from the disease.

The proteins denatured at 600 degrees, so cooking the meat would have little effect.

Compared to CJD, Alzheimer’s is much less infectious. However, an autopsy of 8 people who all received hormone injections from the same donor (who turned out to have Alzheimer’s) showed that they had beta amyloid proteins accumulating in their brain, which is characteristic of the disease.

Research is currently underway to assess whether these results can be replicated. If they can, new sterilisation protocols need to be developed in order to reduce the chance of Alzheimer’s transmission through injections and surgery.

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ARTICLE

A

recent clinical trial holds high hope for a new blood test that will enable faster and more accurate diagnosis of suspected heart failure. The trial was conducted at the University of Edinburgh and funded by the British Heart Foundation.

An

Innovative

Blood Test to

Diagnose

Heart Failure

Acute Coronary Syndrome (ACS) arises from the accumulation of cholesterol in the coronary arteries that supply blood to the heart. This blockage causes a life-threatening deprivation of oxygen resulting in heart failure and cardiac tissue death. ACS is prevalent in the Western world; reports in 2009 revealed around 1 million hospital admissions and 33,000 deaths in that year from ACS. This disease has associated costs of £3.6 billion due to healthcare costs and economic losses. Since 2009, there has been a huge amount of research invested into treatment and diagnosis of ACS.

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The results of this most recent clinical trial were published in October 2015.

Blood taken from patients admitted to hospital with suspected heart failure was analysed using a high-sensitivity cardiac troponin I assay.

Troponin I is one subunit of the “contractile machinery” inside each cardiac cell, and once activated it destabilises to allow interaction of the proteins actin and myosin. The heart is then able to contract and pump blood around the body. Following damage to the heart in ACS, cells of the heart can rupture causing leaking of troponin I into the bloodstream.

It is then possible to detect levels of this protein in blood taken from anywhere in the circulatory system, and these are proportional to the severity of heart failure.

Troponin blood assays have been used in the past as an indicator of heart failure, but this innovative new assay provides a more

a quick, simple and accurate indicator of “ such heart failure may mean that a huge proportion of patients could be sent home much more quickly ” accurate and fast test to indicate the risk of heart failure. The study comprised of more than 6000 patients with suspected ACS admitted to several hospitals. The blood test was able to distinguish two-thirds of patients with less than 5ng/l (nanograms per litre) of troponin I in plasma samples as being “low risk”, who could have been safely discharged from the hospital. The test was accurate to 99.6%. The possibility of such a quick, simple and accurate indicator of heart failure may mean that a huge proportion of patients could be sent home much more quickly than they are now.

This is not only a huge financial benefit to hospitals, but also greatly reduces stress and worry to patients.

There are always limitations to a biomedical diagnostic test, such as the risk of missing a seriously ill patient, therefore it must be used with careful observation of the patient and routine ECG (Electrocardiogram) measurements.

Researchers hope that this assay may be used routinely in hospitals in the future, providing considerably improved patient experience and reducing the financial burden of ACS on healthcare.

Abigail Wils

Abigail Wilson synapsebristol.blogspot.co.uk

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ARTICLE

How Fatty Foods Can Prevent Seizures T

he role of food in curing disease has become incredibly popular.

‘Fad’ diets such as raw veganism and the alkaline diet are constantly being branded as having the ability to cure cancer and a multitude of other diseases. Whilst many justifiably remain sceptical of these brash claims, there is certainly some robust evidence supporting one diet and its ability to treat disease. This diet is the ketogenic diet and it has a fascinating role in preventing one of the most common neurological disorders – epilepsy.

Epilepsy is defined as a tendency to experience recurring (epileptic) seizures. It affects people of various racial, social and geographical groups and is estimated to affect 40 million individuals worldwide. Conventional treatments for epilepsy include antiepileptic drugs (AEDs). AEDs are medications that suppress seizures rather than treat the underlying cause.

Other interventions include surgery and vagal nerve stimulation. Although these treatments are often successful in controlling the frequency of seizures, for many they simply fail to work effectively or the side effects are too severe.

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Whilst many diets, as mentioned before, can be regarded as no more than modern fads with an approximate life span of typically just a few years when it becomes clear that they rarely deliver health benefits, the ketogenic diet has a history that dates back to the 5th century BCE. It was then that Hippocrates noted that a man’s seizures stopped when he abstained from food and drink. It was from this initial observation that the idea for the ketogenic diet was born.

ketogenic diet is “ The essentially a high fat,

low carbohydrate regimen

”

The ketogenic diet is essentially a high fat, low carbohydrate regimen, akin to the Atkins diet. The classical ketogenic diet follows a ketogenic ratio of 4:1, which means that for every 4g of fat consumed, 1g of protein plus carbohydrates can be consumed. The diet emphasises the consumption of naturally fatty foods such as butter, oil and cream and eliminates carbohydraterich food such as bread, rice and pasta.

Only low carbohydrate fruits and vegetables are permitted.

In the ketogenic diet, starvation is essentially being mimicked. There is not enough glucose to meet the energy demands of the body and so an alternative strategy is adopted. Initially the body uses up all of its reserves of blood sugar as energy. The next state involves the body converting glycogen (stored in muscle and liver cells) into glucose for use as an energy source.

Eventually the glycogen supply declines to a low level and the cells have to rely on fat as a source of energy. This leads to ketosis, a metabolic state in which most of the body’s energy supply comes from ketone bodies as opposed to blood glucose.

Interestingly, it is currently unknown as to how elevated levels of ketone bodies in the blood stream help reduce the frequency of seizures in epilepsy sufferers, but research shows that it does work.

A recent study led by the University of Wollongong in Australia was conducted to evaluate the efficacy of the ketogenic diet in young children suffering from epilepsy. The results of this research were positive, with 6% of patients becoming entirely seizure

free and a further 73% experiencing a seizure reduction of 50-90%.

is not enough glucose to “ there meet the demands of the body

�

Although the results for many other studies have been equally successful, the ketogenic diet is still not a commonly considered treatment as for epilepsy.

This may be because the diet itself has its drawbacks. For example, side effects such as constipation, kidney stones and gastro-oesophageal reflux are common which can lead to poor compliance with or termination of the diet.

In a time when cost containment in health care is a growing concern, it is interesting that diet and its association with health outcomes remains poorly endorsed. Future research should endeavour to better understand which potential patients stand to gain most from the diet and remain free of side effects, and to examine how a modification in the diet can limit side effects to level that is more tolerable.

Hannah Koffman synapsebristol.blogspot.co.uk | 11

INTERVIEW

Interview: Dr Paul Race School of Biochemistry

How did you get from your undergraduate degree to where you are now at Bristol?

My first degree was in Microbiology and as part of that I had to do quite a bit of Biochemistry; it became apparent pretty early on that the bit that I liked the most was the biochemical aspects.

After the degree I thought that I’d quite like to do a PhD, and it was the Biochemistry that I was most drawn to, so I did a PhD in biochemistry!

[After my post-doc, next came] applying for independent work. I ended up taking elements of what I’d learnt in my Microbiology degree, what I’d done in my PhD and what I’d done in my post-doc, and brought them together to become what is now my independent research.

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You’re a key member of SynBio [Bristol’s synthetic biology research centre]; how does your work fit into that? What’s your role within the group?

I’m co-director. Part of the activities at the centre are really based around applying synthetic biology approaches to natural product drug discovery and manipulation. This involves doing things such as genome engineering, high throughput screening, DNA synthesis; doing things very quickly in very small volumes to be able to generate lots of useful molecules more quickly, cheaply, and efficiently.

How would you describe your typical day in the lab/university in general?

Would you prefer to stick with your daily routine as it is now, or would you go back to pure research if you could?

I do about three quarters of my teaching in the autumn term, in about a 4-6 week period. This time of year is very teaching and admin focused, but then the rest of the year is much more research based. But when I say research, I mean writing grants and meeting with students and post-docs; I never get in the lab anymore. It’s reached a point where I probably wouldn’t know one end of a pipette from the other these days!

It is different, but not necessarily in a good or a bad way. I still experience research activity by proxy through the people in the lab; PhD students, post-docs, technicians; so I still get to experience the highs when stuff works or when you have an idea and you bring it to fruition… but I guess a good part of it is that I’m a bit more removed from the lows! So I’m not the guy whose transformations aren’t working, I just get to hear about it.

I would say that this is universal to everyone who goes down an academic career route; it happens to them at some stage, some people earlier than others, but there’s no way around that.

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Do you have any advice for someone who is looking to go into a career in research?

If you could do research with anyone, dead or alive, who would it be?

Stick with it. Science can be a cruel mistress!

If it was somebody currently, it would be someone like George Church because he’s a real polymath, someone who brings together lots of different types of scientific ideas from different fields and amalgamates them. He’s also got this real kind of maverick property about him that I really like in people.

He’s really really smart, really sparky but also a bit of a non-conformist!

My personal feeling is that the people who make it aren’t necessarily the most brilliant people, but they’re the people who are willing to hang in there for the long haul. You need that resilience, that ability to withstand disappointment. That’s not to say that it’s an exercise in attrition, but you need to be able to know that not every grant you write is going to get accepted, not every paper that you submit is going to be favourably reviewed. You have to be tough.

If you had to choose the coolest piece of science that you’ve ever done, what would it be?

It would actually be a piece of work that we’ve just done; I submitted the paper this morning and I’m kind of not at liberty to talk about it because it’s super top secret!

But basically, we have discovered an enzyme that does a transformation which nobody believed existed in nature. It’s a transformation that synthetic chemists use all the time, and it’s used in industry to make pharmaceuticals and agrochemicals.

People have been searching for an enzyme that does this reaction for many decades and we think we’ve found it.

That’s really the most exciting thing I’ve done, but then again the reviewers probably won’t like the paper!

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But somebody ever, probably Michaelis and Menten, the kinetics guys. They never get the credit they deserve! Everyone goes on about Watson and Crick, but the impact that their discovery had on biochemical research is tremendous and probably vastly unappreciated nowadays. …Especially by undergraduate biochemists!

Yes! He says as he’s writing his second year data handling questions!

Melissa Levy

A

rtemisinin has proved to be one of the most successful anti-malarial drugs to date, effective against most strains of the Plasmodium falciparum parasite. Yet the ability of this parasite to evolve resistance is well known and has been occurring since the 1950s, with multiple drugs becoming completely ineffective against the disease. An artemisinin resistant parasite first emerged in Cambodia back in 2008, and there have been multiple reports of this resistant parasite occurring across South East Asia.

Very little is known about the transmissive abilities of P. falciparum, the main issue being the risk that it spreads to Africa. The results of this would be disastrous, as the most commonly used anti-malarial drug would become futile.

To gain a deeper understanding of whether this parasite has the potential to spread throughout Africa, a laboratory study was conducted to test the efficacy of its ability to infect non-native mosquito vectors.

Firstly, gametocytes (components of the P. falciparum life cycle which are responsible for disease transmission) were obtained from parasitic isolates from Cambodia. Isolates were used if

ARTICLE

The Risk of Anti-Malarial Drugs Becoming Ineffective they showed artemisinin resistance/ sensitivity in patients or in vitro. These gametocytes were used to infect both native and non-native mosquito vectors, to determine whether only a speciesspecific vector could transmit this parasite or if its transmissive abilities were more widespread.

Results showed that the resistant parasites developed and produced sporozoites (a motile, infective life cycle stage) in the two Southeast Asian vectors, Anopheles dirus and Anopheles minimus. This result was also found in the non-native, most prominent African vector, Anopheles coluzzi. The capability of this resistant parasite to infect such diverse Anopheles vectors poses a large threat of spreading across the globe. This resistant parasite has already undergone a rapid expansion in Cambodia and neighbouring countries.

With these recent problematic findings, there is a great need for subsequent control measures to minimise its spread throughout Southeast Asia, and attempt to halt its impending spread into Africa.

Roisin McDonough synapsebristol.blogspot.co.uk | 15

ARTICLE

PERKINS’ METALLIC TRACTORS

E

lisha Perkins is a relatively wellknown name in the world of medical quackery. Born in Connecticut in 1741, he is remembered for his invention and subsequent peddling of Perkins’ Metallic Tractors, which supposedly manipulated the property of ‘animal magnetism’ to relieve pain and cure disease. He noticed that, during surgery, contact with metal implements often seemed to cause muscles to twitch. After a number of experiments, Perkins decided that he had found the ideal materials for the production of thin needle-like implements which, when drawn across the skin in a stroking fashion, could cure all manner of conditions. Some accounts say that he produced the needles, referred to as Tractors, in his own house in a furnace inside one of the walls. The Tractors were made of iron and brass although Perkins advertised them as being made of more exotic alloys, potentially as a way to secure his patent and make them difficult to reproduce.

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An original set of Metallic Tractors.

Credit: Wellcome Library, London

The Tractors were advertised extensively, and rapidly gained popularity across the United States. Public displays of treatment were frequent, and when Perkins took his invention to Philadelphia, George Washington himself purchased a pair for his family’s use. However, opposition to the Tractors’ use had already been mounting in the Connecticut Medical Society.

Although Perkins had easily swayed both the general population and those in

THE PLACEBO EFFECT REVEALED political positions, the medical community remained unconvinced. In 1796, the Society passed a vote railing against Perkins’ Tractors, which were being sold for 25 dollars per set. The vote was scathing to say the least:

“giving out that such strokings will radically cure the most obstinate pain to which our frame is incident, causing false reports to be propagated of the effects of such strokings, especially where they have been performed on some public occasions, and on men of distinction…this Society announce to the public, that they consider all such practices as barefaced imposition, disgraceful to the faculty, and delusive to the ignorant…”

Unperturbed by such statements, Elisha’s son Benjamin took the Tractors to Britain hoping to find a new audience.

Here they were sold for 5 guineas per set with similar success, and were even advertised in The Times. In 1799 Elisha

travelled to New York hoping to test a new antiseptic during a yellow fever outbreak, only to end up catching the disease and dying about a month after arrival. Shortly afterwards, British physicians also started displaying scepticism of the Tractors, the most notable being the renowned John Haygarth of Bath. At Bristol Royal Infirmary he treated five patients with wooden replicas of the Tractors, and found that they had exactly the same effects, which he then reported in 1800:

“Such is the force of the Imagination!”

Not only had Haygarth performed one of the first single-blind clinical trials, but it was the first demonstration of the placebo effect in action.

James Ormiston

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ARTICLE

CANCER TREATMENT USING PARTICLE ACCELERATORS Laura Rogers

C

ancer will most likely affect you, your loved ones or friends during your lifetime, and while a scary statement, this is why enormous amounts of research and development are invested into potential treatments. Radiation beams from particle accelerators have become a worldwide method of cancer treatment. The most well-known particle accelerator is the Large Hadron Collider (LHC), which is a 27km long underground tunnel based at CERN in Switzerland. It is comprised of rings of superconducting magnets which are cooled to -271.3°C using liquid helium. Therefore it will come as little surprise to you that when particle accelerators were first proposed for use in hospitals there were many doubts about their size, cost and safety. However, Linear Accelerators have become the most common piece of equipment for external beam radiation treatments for cancer.

A Linear Accelerator targets cancerous cells using high energy X-Rays, which damages their DNA. Cells where the DNA is so severely damaged that it cannot repair itself stop reproducing or die; these dead cells are then disposed of by the body.

This means if the tumour is contained, the radiation can kill off the cancerous cells.

However, one nasty side effect is that the radiation can also damage healthy cells. This makes it challenging to target cancers deep within the body.

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New developments in accelerator physics have allowed more optimised treatments to be developed. Hadron Therapy is a developing type of accelerator treatment using beams comprising of charged particles rather than high energy X-Rays.

Charged particles, such as protons and carbon ions, have the beneficial property that they can penetrate body tissue with little diffusion. They deposit the maximum amount of energy at the tumour before stopping, thus minimising interactions with healthy cells. This is especially valuable for young children with tumours, or treatment near critical organs.

The main challenge facing research scientists is producing smaller and cheaper accelerators for Hadron Therapy. In the UK there is only one ‘low energy’ proton beam available for cancer therapy, which is at the Clatterbridge Cancer Centre and is primarily used for the treatment of eye tumours. There are plans to build two ‘high energy’ proton beam facilities to treat more complex cancers, one at UCL hospital and the other at Christie Hospital in Manchester. These facilities should be completed in 2018 costing a total of £250 million. The main benefit of Hadron Therapy is the precise targeting of tumours reducing the risks of damaging healthy cells and other side effects, which is why its development is a high priority in research laboratories across the globe.

Amy Newman

N

anotechnology is a field of science which works on the development of tiny particles smaller than 100 nanometres (nm) in size. One nanometre is a billionth of a metre! Nanoparticles in particular have a unique combination of properties, including their size, large surface area to mass ratio, and high mobility in biological systems. They are also known as “zerodimensional� nanomaterials, as unlike nanotubes or nanowires, all of their dimensions are in the scale of nanometres.

Whilst conducted on a tiny scale, nanotechnology has massive potential to revolutionise many industries, from manufacturing to electronics. In particular, the use of nanoparticles in medicine is a major area of discovery that will transform the way we diagnose and treat disease.

The properties of nanomaterials have been shown to aid us in overcoming some of the downsides and limitations that using traditional techniques can bring.

Areas of medicine where these precisely engineered materials have proven particularly useful so far include medical imaging and drug delivery. They provide exciting opportunities to modify the characteristics of medicines, such as their solubility, half-life in the blood circulation, and ability to cause an immune response.

There are examples of nanomaterials that can lower the toxicity of medical treatments and offer more effective and targeted means of administering drugs; wide uptake of this technology will reduce healthcare costs.

One exciting development in the field was made fairly recently by a team

ARTICLE

NANOPARTICLES IN MEDICINE

of researchers collaborating from across many different departments here at Bristol. Led by Professor Dek Woolfson from the Schools of Biochemistry and Chemistry, they produced a new type of nanoparticle- self-assembling cages of peptides known as SAGEs (for Self-Assembled peptide caGEs). The nanoparticles are only one sheet of molecules thick, and on their surfaces they have nanoscale-sized pores. The particles are able to assemble to form structures which resemble that of viruses.

Crucially however, the SAGEs are not infectious, despite being engineered to become the size and shape of viral particles.

Therefore Professor Woolfson’s team hope that one of the eventual uses of these nanoparticles will be as vaccines. The first stages of carrying on with this work involve experiments in test tubes, using immune system cells. Ultimately they hope to be able to inoculate both humans and other animals against specific diseases such as Dengue fever, which there is currently no vaccine for.

With the Schools of Physics and Chemistry helping out on this project, providing specialised microscopy and structural modelling methods, the creation of SAGEs is a fascinating example of truly interdisciplinary research with many potential medicinal applications.

The growing fields of nanoparticles and nanotechnology have the potential to bring huge positive impacts to the ways in which we treat a wide range of illnesses.

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ARTICLE

the

MOULDY of

TALE

PENICILLIN Aleks Marsh

I

n 1945 Alexander Fleming, Ernst Chain and Howard Florey won the Nobel Prize in Physiology or Medicine ‘for the discovery of Penicillin and its curative effect in various infectious diseases.’ Moulds have been exploited for their antibacterial properties as many as 2500 years ago when civilisations in Egypt and China used mouldy bread and soybeans to treat wounds which were inflamed and pus ridden. It was observed that treatment using mould could reduce swelling and in some cases remove the infection altogether. However, it wasn’t until the discovery of microbes in 1674 by inventor of the microscope, Antoni Van Leeuwenhoek, that the science behind this phenomenon could be properly understood. There are many observations throughout history where mould prevented bacterial growth, but these insights were largely ignored by mainstream medicine.

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Investigation of the efficacy of mould as an antibacterial agent did not begin until 1920, when observations by scientists Gratia and Dath showed the growth of Staphylococcus aureus bacteria was inhibited by mould. In 1928, Fleming observed that his culture of Staphylococcus bacteria had become contaminated by Penicillium, which had destroyed a large portion of it. Fleming named the active ingredient in the mould Penicillin. Fleming continued to work on Penicillin for the next 12 years, and provided cultures to Howard Florey, Ernst Chain, and Norman Heatley at the University of Oxford.

Florey’s group aimed to produce sizable quantities of Penicillin, purify it, elucidate the chemical structure and the bacterial species it was capable of eradicating, and finally quantify the toxicity to humans. Unfortunately the structure of penicillin was unknown and therefore it could not be chemically

synthesised, so Florey’s team worked to improve fermentation methods to yield more of the mould. Ideally, if the chemical structure of penicillin were known it would have been much easier to chemically synthesise, rather than produce litres of the mouldy broth mixture. The chemical structure of Penicillin was not elucidated until 1945

by Dorothy Hodgkin, who used X-ray diffraction, and this discovery won her a Nobel Prize in 1964. The Laboratories for Integrative Neuroscience and Endocrinology at the University of Bristol are based in the Dorothy Hodgkin building.

By 1939 Florey’s group had not made enough Penicillin to save one man: Albert Alexander, a 48 year old police officer who cut his face whilst shaving and developed septicaemia.

On injection with penicillin, dramatic improvements were observed to his condition, but he died shortly afterwards as there was not enough Penicillin to continue his treatment. It would take about 2000 litres of mould broth per patient per day to treat an infection effectively using Penicillin, and this dosage should continue for around a week to ensure that the infection has been thoroughly quashed.

The Oxford group had the potential to eradicate unnecessary deaths from bacterial infections but not enough money, resources or equipment to make this a reality.

In 1941 Florey’s team asked the US government for help to commercialise penicillin. They argued that Penicillin could be used to save the lives of soldiers fighting in WWII from preventable deaths by infection. The US government financed the production of Penicillin by fermentation at the National Research Laboratory in Illinois. They also sourced help from several pharmaceutical companies including Merck and Company and the Pfizer Drug Company, among others.

Initially the companies were reluctant to divulge scientific developments in the fermentation process to one another, however they quickly realised it was better to cooperate with one another for the sake of the war effort.

In 1942, patient Anne Miller’s life was the first to be saved from a Streptococcal infection using Penicillin, and since then countless lives have been saved since using antibiotics, perhaps even yours. The successful commercialisation of Penicillin is an important lesson in how scientists, the pharmaceutical industry and government can work together to accomplish endeavours which may be beyond their own personal gains, for the good of us all. This is certainly something that we as a society should learn from when facing future problems such as antibiotic resistance.

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ARTICLE

S I M U L ATE D G U I LT Yhe misses a shot while you’re playing FIFA, or even when

ou may not think twice about hurling abuse at Rooney when

shooting a civilian in the face in Grand Theft Auto. But one day, you could be made to.

The Rise of Artificial Intelligence Modelling the neuronal networks in the brain is done for a range of reasons, spanning across all branches of science. If you were to have a computerised brain consisting of all of our 100 billion or so neurons you can, in theory, identify psychiatric disorders, model drug treatments and provide it a format of communication: and now you have generated your own Artificial Intelligence (AI).

This may seem like science fiction (as depicted in films such as Her), but a survey done by the Future of Humanity Institute in Oxford estimates that human-level AI will be achieved within this century. This would certainly raise ethical and philosophical questions, which must be answered before we can proceed further with investigations of AI. However, we have some time

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yet. Work on the creation of a virtual nematode C. elegans with just 302 neurons is still ongoing, but headway is being made as the Human Connectome Project aims to model all long axonal connections in the healthy human brain.

Ethical Dilemma The most important of questions, in my opinion, is to understand how these beings of Artificial Intelligence perceive the world around them: are they conscious? If they have no mechanisms to truly ‘feel’ emotions, can they be considered as counterparts to human intelligence? If they are just simulations, then does turning off the computer ‘hurt’ them? If not, this gives us endless opportunities to carry out research. This could include having free reign to test how modifying brains may

affect different disorders, whether drug treatments are effective, and even the possible application of AI in computer games to create extremely realistic, yet non-human, avatars.

However, if there were the possibility that AI do have some sense of feelings, then how do we condone torturing these simulations? Should we set up thousands of others and treat them well to outweigh the pain we cause the few, or apply real animal testing guidelines?

If the gaming industry begins using human-level AI—with sentient, intelligent and aware computerised simulations—perhaps in the form of a civilian walking the streets of San Andreas, you’ll have to adjust your playing style.

Ode to Turing My hope is that such ethical questions will not ignored and accepted as merely rhetorical, but rather generate thought about the state of being and sentiency encompassed within AIs and other such simulations. The irony however lies in the fact that these questions could well be answered by simply loading up a model of your own brain and asking it—I feel a Turing test coming on…

James Portman

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ARTICLE

‘Sleepy Heads’

OCH3

Sleep for Students H N

O

A

CH3

s winter approaches and the days are shortening, we rediscover our need for sleep. But don’t panic! It’s not unnatural to feel like those 9 a.m.’s are more and more impossible to attend as the days darken. It appears that due to a hormone called melatonin, you may have more justification for remaining under the duvets than your lecturers would let you think.

Melatonin is a ubiquitous hormone, acting slightly like a neurotransmitter, and is released primarily from the pineal gland in the brain. It provides the body with a representation of the dark, aiding the process of falling to sleep, and when this is disrupted, it can have severe consequences such as jet lag, prolonged insomnia, depression and even cancer.

The circadian rhythm, colloquially known as ‘the body clock’, regulates our bodily processes such as hunger and sleep patterns. The study of the circadian rhythm is called chronobiology, from ‘chronos’, the

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NH

Greek word for ‘time’. The major structures of the biologic clock system include the pineal gland, the eyes, skin and the suprachiasmatic nucleus (SCN) of the hypothalamus in the brain.

The amino acid tryptophan is only converted to melatonin when it is dark. During hours of darkness, the pineal gland is stimulated to produce melatonin, inducing sleep. On the other hand, during the day, the lightsensitive layer in the eye called the retina converts the stimulus into an electrical impulse that travels to the hypothalamus in the brain. The hypothalamus relays another message to the pineal gland, down-regulating melatonin production.

Principally, melatonin is supressed by blue light (wavelengths of around 460 to 480 nm), depending on the intensity of the light source and the length of exposure. Sunlight expresses all wavelengths in equal intensities.

In the past, our ancestors would have been exposed to less blue and more

yellow and red light in the evening hours from campfires and lamps. In these periods sunlight would therefore be the key provider of the crucial frequencies required to instigate melatonin breakdown and promote wakefulness. Melatonin levels are low in the early hours of the morning once sun rays provide blue light, degrading this hormone naturally. As the sun sets, our bodies detect less blue light so that melatonin levels rise in our blood plasma, helping us to fall asleep.

Consequently, when there are fewer hours of sunlight, more melatonin is produced.

Melatonin can act as an effective antioxidant by reacting with highly reactive free radicals directly, such as the oxygen and nitrogen species; OH•, O•2−, and NO•. It is able to react with a broad range of such reactive species within most tissues, making it a better antioxidant than others, including vitamins C and E, especially against mitochondrial oxidative stress.

Natural sources of food that help us obtain tryptophan, the precursor amino acid for melatonin, include pineapples, cherries, walnuts, oats, bananas, sweet potatoes, pearl barley and rice.

These foods also contain beneficial carbohydrates for serotonin production and are a source of antioxidants, fibre and several other vitamins and minerals.

During the last few decades, the incidence of sleep-onset insomnia has increased substantially among

adolescents. People of this age-range need at least 9 hours of sleep a night to function optimally. Teenagers typically feel tired and ready for sleep later than adults, hence their reputation for sleeping in. Young infants do not produce melatonin in a circadian-like cyclical manner until they are three months old. Meanwhile, children aged 1-5 were shown to have the highest levels of night-time melatonin.

Researchers believe these levels drop as we age. Some think that lower levels of melatonin may explain why a proportion of older adults have sleep problems and tend to go to bed and wake up earlier than when they were younger.

Habit changes that are affecting our sleep patterns include increased reliance on electronic screens and the rising popularity of coffee consumption in the Western world. Drinking coffee, even up to twelve hours (double the half-life of caffeine) before bed, rewinds the body’s circadian clock by up to an hour, mimicking the symptoms of jet lag.

Studies suggest that melatonin supplements may help people with disrupted circadian rhythms - such as those with jet lag, night shift workers, and seniors, to sleep better. However, for anyone who is not suffering from jet lag or a sleep deprivation disorders, melatonin supplementation can do more harm than good by drastically disrupting our vital circadian rhythm.

Lydia Melville &

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Did you know... ...that every atom in your body is replaced over the course of seven years?

The cells in your body are metabolising, respiring and biosynthesising all of the time, using the food and drink that you ingest to do so, and expelling useless by-products. When cells die, they are removed as well.

The rates at which whole cells are replaced can vary between different cell types. For example, sperm cells will die after around 3 days, red and white blood cells will die over the course of a year, and the irreplaceable neurons in your cerebral cortex are with you until the end!

David Morris

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