BioScience Today 19

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ISSUE19

dementia • big interview • infection prevention • gene therapy • genome reprogramming • genome mapping • drug delivery

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foreword 21st century breakthroughs Helen Compson Editor in chief

Editor

We report on some incredible, bound-breaking developments this issue, one of the best the breakthrough by a research team at the Massachusetts Institute of Technology.

Design

While perfecting a machine-learning platform designed to seek out alternative antibiotics, they discovered a powerful new compound that, in laboratory tests, killed many of the world’s most problematic disease-causing bacteria including some strains that are resistant to all known antibiotics.

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Their vision is writ large. Prof. James Collins said: “We wanted to develop a platform that would allow us to harness the power of artificial intelligence to usher in a new age of antibiotic drug discovery.”

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Meanwhile, a Harvard University team has ushered in nothing less than a paradigm shift with its new approach to diagnosis ‘on the shop floor’.

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Closing that gap between presentation of symptoms and the confirmatory lab results coming back, genomic neighbour typing enables medics to infer the type of bacteria most likely at work in their patients within minutes of sequencing.

For some patients, the speedy approach will be a life-saver. For the world at large, it will reduce the reliance on broad-spectrum antibiotics, thereby aiding in the fightback against drug resistance.

Distinctive Publishing or BioScience Today cannot be held responsible for any inaccuracies that may occur, individual products or services advertised or late entries. No part of this publication may be reproduced or scanned without prior written permission of the publishers and BioScience Today.

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In the field of cancer research, a team at University College London has achieved another first, this time deciphering how millions of individual cells communicated with each other in laboratory-grown tumours.

The hope is this new-found understanding will reveal how some tumours are able to evade the immune system and become resistant to treatment and, as a result, enable the development of new, more effective drugs.

However, our main focus this edition is on the trillion-dollar scourge that is dementia.

That was 2018’s assessment of the annual financial burden it places on global healthcare services and economies, a figure expected to rise to $2tn by 2030.

But dementia and its causes are an incredibly complex affair, so much so that no new approved drug therapies have been produced for Alzheimer’s, the most common form, since 2003. The reason? Until very recently, the clinical trial failure rate was running at a horrifying 99.6%!

Turn to page 16 and you can read all about dementia-diagnostics firm Cytox’s mission to turn the situation around.

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features

Artificial intelligence yields new antibiotic.

A deep-learning model identifies a powerful new drug that can kill many species of antibiotic-resistant bacteria.

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26 Tackling the trillion dollar Alzheimer’s disease Tabby cat or tiger? Medics need to be fleet of foot when it comes to determining whether they are dealing with something tame or wild, but the traditional route to identifying bacteria takes time.

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contents / www.biosciencetoday.co.uk / issue 19 /

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Foreword

4-5

Contents

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Biodigestables

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Industry Contributors

10-15

News

16-23

dementia Tackling the trillion dollar Alzheimer’s disease

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Build-up of brain proteins affects genes in Alzheimer’s disease

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big interview The traditional route to identifying bacteria takes time. Now a team of Harvard researchers is aiding the fightback against drug resistance. Helen Compson talks to Bill Hanage, Associate Professor of Epidemiology of Harvard University to get his insight

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infection prevention A deep-learning model identifies a powerful new drug that can kill many species of antibiotic-resistant bacteria.

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intellectual property Shanks v Unilever – An opening of the claim floodgates?

Are your innovations protected? Innovation is something that defines the biosciences sector.

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gene therapy New Cell and Gene Therapy Catapult CEO brings continuity and ambition

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genome reprogramming Hyperactive FOXA1 reprograms endocrine-resistant breast cancer to become metastatic

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genome mapping Unprecedented exploration generates most comprehensive map of cancer genomes to date

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Training and Education The hidden way to fill vacancies, train and retain

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drug delivery Next chapter of Intarcia’s mini pump for diabetes begins

Unprecedented exploration generates most comprehensive map of cancer genomes to date

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BIODIGESTABLES

GENETIC ‘CLOCK’ PREDICTS LIFESPAN IN ANIMALS Researchers at CSIRO, Australia’s national science agency, have discovered a simple way to estimate how long a species lives.

New study proves AI can accurately identify UK’s 5th most common cancer New evidence published in leading medical journal JAMA shows that people with suspected skin cancer could be diagnosed using AI technology DERM, with the same accuracy as clinical specialists.

In a study of over 1500 patients, DERM successfully identified 100% of melanomas, with over half in the earliest stage of malignancy. Early and accurate diagnosis of skin cancers increases chances of survival by 87%.

Every year, around 16,000 people in the UK are diagnosed with melanoma, which is an aggressive form of skin cancer. As the fifth most common form of cancer in the UK, the incidence has doubled in the last ten years alone and approximately 2,300 people die annually of the disease.

Alcohol tolerance may have saved apes Decline linked to climate change

The ability to process alcohol may have saved humanity’s ancestors from extinction, a new book ‘Humans and alcohol: a long and social affair’, suggests.

Climate change could be responsible for a substantial decline in populations of shorebirds, say researchers at the University of Bath, following a study published in Science analysing population data over a period of 70 years.

About ten million years ago, our African ape ancestors were eating fallen fruits on the forest floor – many of which would have begun to ferment and become alcoholic.

However an international team of researchers, including from the Universities of Bath and Sheffield, have found that rates of daily nest predation have increased globally, but this is particularly marked in the Arctic, where they have increased threefold in the last 70 years.

At the time, ape populations were crashing in the face of competition with monkey species which were able to eat unripe fruit – which apes, like humans, struggle to digest.

Monkeys are unable to tolerate the ethanol in such fruits, and this new source of calories might have brought apes back from the brink.

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Using the human genome, the researchers found the maximum natural lifespan of humans is 38 years, which matches anthropological estimates of lifespan in early modern humans.

This has been extended over the centuries by changes in lifestyle and more recently by advances in medicine.

The discovery has revealed the lifespans of extinct species such as woolly mammoths and Neanderthals. It also benefits fisheries and conservation management, which until now have relied on observing how long animals live in the wild.

Bowel cancer rates after colonoscopy vary by provider A colonoscopy is the main test used to detect bowel cancer, but like most tests, it is not always 100% accurate and cancers can be missed.

New research led by the University of Leeds looked at the number of patients whose colonoscopy found no evidence of bowel cancer, but who were subsequently diagnosed with the disease.

They found that overall the rate of these post-colonoscopy bowel cancers decreased in England. However, they found that the rates of these potentially missed cancers were lower for colonoscopies performed by the NHS than those performed by independent providers on behalf of the NHS.

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BIODIGESTABLES

New chair for joint steering committee The European Laboratory Research & Innovation Group (ELRIG) UK and the British Pharmacological Society, today announced that Dr Ann Hayes has been selected to chair their joint steering committee. Dr Hayes will lead the committee to help ensure both organisations meet the objectives of the newly formed strategic alliance, which aims to bring new opportunities for education and networking in UK drug discovery and pharmacology.

Worldwide more than 140,000 people died from measles in 2018, according to new estimates from the World Health Organization (WHO) and the United States Centers for Diseases Control and Prevention (CDC). These deaths occurred as measles cases surged globally, amidst devastating outbreaks in all regions.

Most deaths were among children under 5 years of age. Babies and very young children are at greatest risk from measles infections, with potential complications including pneumonia and encephalitis (a swelling of the brain), as well as lifelong disability - permanent brain damage, blindness or hearing loss.

is vaping safe?

New technique unlocks secrets In a new paper published in the journal Nature Communications, researchers from the Universities of Glasgow and Edinburgh describe how they have developed a new method to capture 3D video images of the growing hearts of zebrafish embryos for the first time.

Zebrafish hearts are surprisingly similar to those of humans, making them useful in cardiac research. The British Heart Foundation – one of the funders of the study – hope that the new method of visualising zebrafish hearts will provide scientists with valuable new insights into the cellular and subcellular processes which occur during the earliest stages of heart development.

Researchers from Queen’s University Belfast have discovered that bacteria often found in the lungs became more harmful and caused increased inflammation when they were exposed to e-cigarette vape.

The results of the three-year study, published in Respiratory Research, show that this increase in lung inflammation is due to bacteria made more virulent by exposure to e-cigarette vapour.

Dr Deirdre Gilpin, researcher and lecturer from the School of Pharmacy at Queen’s University and lead author of the research explains: “Bacteria have long been associated with the development of lung diseases such as bronchitis and pneumonia where smoking plays a role. Our study is the first of its kind which aimed to compare the effect of cigarette smoke and e-cigarette vapour on key lung bacteria.”

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urine test could revolutionise diagnosis A simple urine test under development for prostate cancer detection can now use urine samples collected at home according to new research from University of East Anglia and the Norfolk and Norwich University Hospital.

This is an important step forward, because the first urination of the day provides biomarker levels from the prostate that are much higher and more consistent. And the research team hope that the introduction of the ‘At-Home Collection Kit’ could revolutionise diagnosis of the disease.

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Send them to our Editor, Ellen Rossiter, at ellen.rossiter@distinctivepublishing.co.uk

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measles cases surge worldwide

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Varuni Paranavitane IP Solicitor, AA Thornton Varuni is an IP solicitor advising on rights in relation to patents, trade marks, designs, copyright. She has IP experience in a variety of industry sectors including fashion, life sciences, digital media, sports and food & drink. Varuni’s practice also includes non-contentious brands advisory work, enforcement strategy, settlement and coexistence strategy advice as well as advice in relation to commercial transactions. Varuni has had litigation experience in courts in the UK as well as coordinating multi-jurisdictional pharmaceutical disputes across the globe.

Bill Hanage Associate Professor of Epidemiology, Harvard University An Associate Professor of Epidemiology at Harvard University and a faculty member of its Center for Communicable Disease Dynamics, Bill Hanage employs a mix of theoretical and laboratory work to research the evolution and epidemiology of infectious disease.

After his PhD, he carried out post-doctoral study at Oxford University and Imperial College London, before being awarded a Royal Society University Research Fellowship.

Tony Hill Chief Commercial Officer, Cytox Tony Hill has been involved in the diagnostics and molecular life sciences industry for 30 years, with especial experience in restructuring and growing domestic and international markets. He has held senior roles in sales and marketing in international diagnostics and molecular life science companies including TwistDx Ltd (part of Abbott Diagnostics), Diasorin Molecular, Innogenetics and Sigma-Aldrich.

In 2012, he was presented with both the Fleming Prize for research in microbiology and the ICAAC Young Investigator Award by the American Society for Microbiology.

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NEW TECHNIQUE ALLOWS SCIENTISTS TO ‘LISTEN IN’ ON CANCER CELLS Scientists have a developed a new technique to decipher how millions of individual cells are communicating with each other in miniature tumours grown in the lab, known as organoids, according to new research published in Nature Methods.

This is the first time that scientists have been able to analyse many different signalling molecules at once in individual cells within replicas of patients’ tumours. Understanding how cells communicate could reveal how tumours are able to evade the immune system and become resistant to treatments.

This could allow scientists to develop more effective new drugs, by revealing why tumours respond the way they do to treatments. It could also help doctors to select the best course of treatment for each individual patient, by testing treatments on a bespoke replica of a patient’s tumour before prescribing them.

The technique rapidly analyses each individual cell in an organoid, looking for the presence of specific signalling molecules – messages that cells send to neighbouring cells, telling them how to behave.

Dr Chris Tape, lead researcher of the study at UCL, said: “Organoids are already revolutionising cancer research by allowing us to test whether experimental new drugs are effective on lifelike models of tumours. But crucially, this new technique helps scientists to understand why a treatment works or not, by revealing in unprecedented detail how cells are talking to each other”.

In order to listen in on cancer cells, the team grew organoids in the lab. These are self-organising 3D structures made up of cancer cells alongside other types of cells, such as immune cells and connective tissue. They mimic the behaviour of cancer in the human body much more accurately than cells grown in a dish.

They then modified a complex technique called mass cytometry, which is used to detect and analyse protein

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molecules. The organoids were broken up into individual cells, then antibodies combined with heavy metal atoms were added. Antibodies are proteins that selectively bind to certain cancer signalling molecules. The scientists nebulised the cells, to convert them into a fine mist, and electrically charged the heavy meal atoms, so that a magnetic field could be used to separate out the different signalling molecules.

The researchers tested this technique in bowel cancer cells and were able to simultaneously detect 28 key signalling molecules, across 6 different cell types, in over 1 million cells. They found indications that the cancer cells themselves, as well as immune cells and connective tissue, had ‘rewired’ the normal signalling networks of bowel tissue, allowing tumours to grow unchecked.

The next steps will be to use this technique to look for ways to block the communications between cells that allow them to withstand treatment. The team also hopes to test this new technique in different types of cancer.

Dr Emily Armstrong, research information manager at Cancer Research UK, said: “Having a better understanding of this complex communication between cancer cells and other types of cell that make up a tumour could reveal secrets of how cancer comes back after treatment and spreads around the body.

“While this technique is in the early stages of development right now, in the future we may be able to grow replicas of individual patients’ tumours, to identify early signs that a drug won’t work for them so we can personalise their treatment plan. We hope this could one day help more people to survive cancer”.

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Bionic hand made in 10 hours thanks to WMG, University of Warwick A 3D printed bionic hand can be made to measure thanks to engineers at WMG, University of Warwick and a collaboration of other companies.

The 3D printed hand incorporates muscle sensors to control an articulated thumb, enabling it to function similar to a human hand.

It can be made to measure in 10 hours in a choice of colours.

© Iterate UK/Ambionics A bionic hand can be made to measure in 10 hours and can grip using a moveable thumb. Designers and engineers from WMG, University of Warwick and UK industry, have been able to entirely 3D Print the device with embedded electrical circuitry to seamlessly connect sensors and actuators.

The IMPACT project, led by Iterate Design and Innovation Ltd, in collaboration with WMG, University of Warwick, C Enterprise (UK) Ltd and Printed Electronics Ltd, was made possible thanks to a grant of nearly £900,000 from Innovate UK, with the aim of developing a 3D printing technology with the ability to print plastic products with integrated electrical circuitry, a capability which they have demonstrated in a bionic hand.

The IMPACT hand has taken inspiration from a similar model developed by Ambionic’s Ben Ryan, whose son had his forearm amputated after birth, and who decided to make him a new one.

The IMPACT team have taken this design further by embedding the electrical circuitry linking the motion controlling muscle sensors with the motors and battery into

“WMG are delighted to be a partner in the IMPACT project, helping to deliver this innovative and revolutionary technology, which is undoubtedly helping put UK PLC at the forefront of 3D Printing research and development globally.”

the structure of the bionic hand, thus providing a durable and aesthetic solution.

Engineers at WMG, University of Warwick have tested the durability of the printed electrical circuitry to understand how well they will endure the bending and flexing that they might experience in use.

They also developed a website so that people can interact with the manufacturers to order a 3D Printed hand, allowing them to insert the measurements of their arm, and select what colour they want their hand to be, providing them with a tailored and personalised product.

10 hours later the hand will be printed with the sensors inbuilt ready for use.

Within the project, Iterate Design and Innovation Ltd developed the design of the hand, including the integration of the electrical circuitry and sensors. Printed Electronics Ltd developed the technology for printing the electrical circuitry within the 3D Printing process and C Enterprise (UK) Ltd developed the multi-axis, multi-material 3D printer that enables the hand to be realised in 3D. Dr Greg Gibbons of WMG University of Warwick comments: “WMG are delighted to be a partner in the IMPACT project, helping to deliver this innovative and revolutionary technology, which is undoubtedly helping put UK PLC at the forefront of 3D Printing research and development globally.”

Gethin Roberts, Project Lead and MD of Iterate Design + Innovation comments: “The IMPACT project has resulted in the creation of an exciting new technology that has the ability to print electro-mechanical parts and assemblies, which weren’t previously possible. Through laying down conductive ink tracks within polymer structures means that parts produced are fully functional straight off the machine bed; offering huge productivity benefits.”

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Project to predict cardiovascular events receives Heart Research UK grant A project at the University of Manchester aiming to develop a new tool for predicting the risk of a cardiovascular event or death in patients who have already suffered a heart attack has received a grant of almost £150,000 from national charity Heart Research UK. In the UK, around 7 million people are living with cardiovascular disease (CVD), which is responsible for one in four deaths.

People with CVD are up to five times more likely to have a stroke, are six times more likely to die compared to those without, and up to half of them suffer a second heart attack.

There are currently no methods to predict the risk in this group of patients, so there is an urgent need for such tools to help assess the risk of future cardiovascular events and deaths in patients who already have CVD.

“This will not only help to improve their quality of life, but could ensure that patients receive care tailored to their condition, increasing its effectiveness and helping to reduce the strain on our health service.”

Kate Bratt-Farrar, Chief Executive of Heart Research UK, said: “We are delighted to be supporting the work of Prof Mamas and his team, which has the potential to have a big impact on how effective we can be at preventing people suffering from a cardiovascular event.

“Our Translational Research Project Grants are all about bridging the gap between laboratory-based scientific research and patient care - they aim to bring the latest developments to patients as soon as possible.

The project, which will be led by Prof Mamas Mamas, Professor of Cardiology at Keele University and Honorary Professor of Population Health at the University of Manchester, will use medical data to develop a tool that predicts the risk of a future cardiovascular event or death, in people who have already had a heart attack with the aim of improving care of patients with CVD.

“The dedication we see from UK researchers is both encouraging and impressive and we at Heart Research UK are proud to be part of it.”

The £147,816 Translational Research Project grant was awarded to the University of Manchester as part of Heart Research UK’s annual awards for research into the prevention, treatment and cure of heart disease.

The development of such a tool would improve the quality of care for patients with CVD by helping GPs to identify patients at higher risk of future cardiovascular events and death, meaning that lifestyle changes can be made or appropriate medical treatment given to reduce their risk.

Prof Mamas said: “This is an incredibly exciting project that we hope will be able to make a real difference to survivors of heart attacks. If we can accurately predict the likelihood of them suffering another cardiovascular event, then we can intervene early and hopefully reduce their risk.

Last year, Heart Research UK awarded more than £1.6 million in grants for medical research projects across the UK. To date, the charity has invested more than £25 million in medical research via its grants programme.

“This is an incredibly exciting project that we hope will be able to make a real difference to survivors of heart attacks. If we can accurately predict the likelihood of them suffering another cardiovascular event, then we can intervene early and hopefully reduce their risk.

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Testosterone levels affect risk of metabolic disease and cancers Having genetically higher testosterone levels increases the risk of metabolic diseases such as type 2 diabetes in women, while reducing the risk in men. Higher testosterone levels also increase the risks of breast and endometrial cancers in women, and prostate cancer in men.

The findings come from the largest study to date on the genetic regulation of sex hormone levels, published in Nature Medicine and led by researchers from the Medical Research Council (MRC) Epidemiology Unit at the University of Cambridge and the University of Exeter. Despite finding a strong genetic component to circulating testosterone levels in men and women, the authors found that the genetic factors involved were very different between the sexes.

The team used genome wide association studies (GWAS) in 425,097 UK Biobank participants to identify 2,571 genetic variations associated with differences in the levels of the sex hormone testosterone and its binding protein sex-hormone binding globulin (SHGB).

The researchers verified their genetic analyses in additional studies, including the EPIC-Norfolk study and Twins UK, and found a high level of agreement with their results in UK Biobank.

The team next used an approach called Mendelian randomisation, which uses naturally occurring genetic differences to understand whether known associations between testosterone levels and disease are causal rather than correlative. They found that in women, genetically higher testosterone increases the risks of type 2 diabetes by 37 per cent, and polycystic ovary syndrome (PCOS)

by 51 per cent. However, they also found that having higher testosterone levels reduces T2D risk in men by 14 per cent. Additionally, they found that genetically higher testosterone levels increased the risks of breast and endometrial cancers in women, and prostate cancer in men.

Dr John Perry from the MRC Epidemiology Unit at the University of Cambridge, and joint senior author on the paper, says: “Our findings that genetically higher testosterone levels increase the risk of PCOS in women is important in understanding the role of testosterone in the origin of this common disorder, rather than simply being a consequence of this condition.”

“Likewise, in men testosterone-reducing therapies are widely used to treat prostate cancer, but until now it was uncertain whether lower testosterone levels are also protective against developing prostate cancer.

Our findings show how genetic techniques such as Mendelian randomisation are useful in understanding of the risks and benefits of hormone therapies.”

Dr Katherine Ruth, of the University of Exeter, one of the lead authors of the paper, added: “Our findings provide unique insights into the disease impacts of testosterone. In particular they emphasise the importance of considering men and women separately in studies, as we saw opposite effects for testosterone on diabetes. Caution is needed in using our results to justify use of testosterone supplements, until we can do similar studies of testosterone with other diseases, especially cardiovascular disease.”

Katherine S Ruth, Felix R Day, Jessica Tyrrell et al. Using human genetics to understand the disease impacts of testosterone in men and women. Nature Medicine; 10 February 2020; DOI: 10.1038/s41591-020-0751-5

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Good blood supply in fat could explain ‘fat but fit’ paradox Improving blood supply to fat could help to prevent heart disease.

‘brown’. Brown fat burns calories to generate heat, helps to control blood sugar, blood pressure and cholesterol levels, and protects against the furring of arteries.

The ‘fat but fit’ paradox – where some people who are overweight have a seemingly healthy metabolism – may be explained by a good blood supply to their fat cells, according to new research funded by the British Heart Foundation.

The researchers now hope to use these insights to help develop drugs which can hijack this process and protect the heart and circulation.

The research – which suggests encouraging the growth of new blood vessels in fat could offer some protection against heart attacks and strokes – is being presented at the American Heart Association Scientific Sessions in Philadelphia, and has been awarded the best UK abstract at the conference.

Scientists from the University of Leeds have studied a receptor– known as IGF1-R – that plays a role in the growth of new blood vessels. The team showed that the removal of this receptor in cells lining the inside of blood vessels of mice fed a high-fat diet encouraged the growth of new blood vessels into fat. This was followed by beneficial changes to the fat, which may offer protection against heart and circulatory diseases in the long term.

According to the researchers, poor blood supply to fat can switch it into an ‘unhealthy’ state. Under these conditions, the fat cells release inflammatory signals that can promote the development of diabetes, high blood cholesterol and high blood pressure, which can all lead to furring of our arteries - the underlying cause of most heart attacks and strokes.

The researchers believe that blood vessels in fat release bioactive chemicals which encourage the fat cells to

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Dr Natalie Haywood, Postdoctoral Research Fellow at the University of Leeds who led the study said: “It’s a myth that you can be overweight and completely healthy – but there may be some truth to the ‘fat but fit’ paradox. People with better blood supply to their fat may be more metabolically healthy and could be protected against heart and circulatory diseases.

“The next step is to identify the healthy bioactive signals released by blood vessels so that we can potentially harness them to combat heart and circulatory disease in obesity.”

Professor Metin Avkiran, Associate Medical Director at the British Heart Foundation said: “All of the cells in our bodies need a good blood supply to stay healthy – and that includes fat cells. If our diets are high in fat, we may risk storing up fat more quickly than our bodies can build new blood vessels.

“Fat is an essential part of our diet, but too much of it can cause a wide range of health issues. This research may explain why some people who are overweight are more at risk of heart and circulatory disease than others.

It’ll take a lot more research before we have a new drug to keep these fat cells healthy. For most people, with or without obesity, the best medicine will be a healthy diet and active lifestyle.”

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Skin cancer diagnosis apps are unreliable and poorly regulated Smartphone apps used as ‘early warning systems’ for skin cancer are poorly regulated and frequently cannot be relied upon to produce accurate results, according to new analysis by experts at the University of Birmingham.

Skin cancer detection apps are designed to ensure that the right people seek medical attention by providing a risk assessment of a new or changing mole. These apps use specialised algorithms to try to detect possible skin cancers.

Researchers based in the University of Birmingham’s Institute of Applied Health Research in collaboration with the Centre of Evidence-Based Dermatology at the University of Nottingham have analysed a series of studies produced to evaluate the accuracy of six different apps. Their results, published in The BMJ, reveal a mixed picture, with only a small number of studies showing variable and unreliable test accuracy among the apps evaluated.

Skin cancer has one of the highest global incidences of any cancer. Early detection and treatment, particularly of melanoma, can improve survival. According to this new analysis, however, apps may cause harm from failure to identify potentially fatal skin cancers, or from overinvestigation of false positive results – for example removing a harmless mole unnecessarily.

The research team was also concerned by the quality of the studies themselves, which evaluated apps using images taken by experts rather than by app users. In addition, many studies did not identify whether lesions identified as ‘low risk’ by the apps were in fact benign, further compromising the conclusions that can be drawn from the evaluations.

Lead researcher Dr Jac Dinnes, of the Institute of Applied Health Research at the University of Birmingham, said: “This is a fast-moving field and it’s really disappointing that there is not better quality evidence available to judge the efficacy of these apps. It is vital that healthcare professionals are aware of the current limitations both in the technologies and in their evaluations.”

The authors also drew attention to the regulations governing the evaluation of healthcare apps. Manufacturers can currently apply CE marks to smartphone apps without necessarily being subject to independent inspection by bodies such as the UK Medicines and Healthcare Products Regulatory Agency (MHRA). Although this may change with new Medical Device Regulations coming into force in 2020, the researchers noted that stricter assessment processes in operation in the US has resulted in no skin cancer assessment apps receiving regulatory approval.

Co-author Jon Deeks, Professor of Biostatistics in the Institute of Applied Health Research, adds: “Regulators need to become alert to the potential harm that poorly performing algorithm-based diagnostic or risk monitoring apps create. We rely on the CE mark as a sign of quality, but the current CE mark assessment processes are not fit for protecting the public against the risks that these apps present.”

Dr Dinnes added: “As technologies continue to develop, these types of apps are likely to attract increasing attention for skin cancer diagnosis, so it’s really important that they

are properly evaluated and regulated. Of course, we also need to emphasise how important it is to go and see your GP if you have concerns – regardless of what an app might tell you.”

The team also has made a series of recommendations for future studies of smartphone apps: Studies must be based on clinically-relevant population of smartphone users who may have concerns about their risk of skin cancer All skin lesions identified by smartphone users must be included – not just those identified as potentially problematic Clinical follow-up of benign lesions must be included in the study to provide more reliable and generalizable results.

Hywel Williams, Professor of Dermatology at the University of Nottingham who collaborated on the study, said: “Although I was broad minded on the potential benefit of apps for diagnosing skin cancer, I am now worried given the results of our study and the overall poor quality of studies used to test these apps. My advice to anyone worried about a possible skin cancer is ‘if in doubt, check it out with your GP’.”

The research was supported by the NIHR Birmingham Biomedical Research Centre and is an update of one of a collection of reviews funded by the National Institute for Health Research through its Cochrane Systematic Review Programme Grant.

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Edible insects: Mealworms on your menu?

Cricket brownies and “chocolate chirp cookies” were served at a meeting about the future of edible insects.

“If you tried an insect-based food, could you tell the difference? Would you know what you were eating? Would you care?” she asked.

Insects are eaten in many parts of the world, and if people in countries such as the UK and US could get over the “yuk factor” it would open a “new frontier in food”, experts said.

Dr Champion said mealworm production requires one twelfth of the food and 2,000 times less water than producing the same quantity of beef, with greenhouse gas emissions 100 times lower.

Insects are a rich source of protein and can be produced using far less land and water – and with a far smaller carbon footprint – than meat such as beef.

Insects can be fed on waste products such as used grain from breweries – another benefit both financially and environmentally.

Scientists, insect producers and other experts discussed the key issues at the University of Exeter’s Penryn Campus in Cornwall last week.

Professor David Hosken, also of the University of Exeter, said sustainability is becoming increasingly important to today’s youth.

“We have got to stop seeing this as a novelty,” said Stefano Pascucci, Professor in sustainability and circular economy at the University of Exeter.

He said retailers will respond to customer demand – so insects could become a more common sight on the shelves of your local supermarket.

“Insects are commonly eaten around the world, but they’re not really part of the food culture in the West.

Ed Tomlin, Director of Six Feet Farms, which breeds crickets for food products, said insect-based food is a “fledgling industry” but he hopes his firm is “ahead of the curve”.

“If we could get over this disgust and neophobia (fear of new things) we could open a new frontier in food.”

Insect-based foods served at the event included both whole insects and products such as brownies, cookies and crackers.

The latter approach – where insects are not visible in their original form – might be more palatable to consumers, according to Dr Olivia Champion, founder of University of Exeter company Entec Nutrition, which is developing insect-based foods.

He said Six Feet Farms focusses on products made from cricket powder, as this helps avoid the “yuk factor” some people feel about eating insects.

The meeting, in December, also heard about the potential to increase the use of insects as feed for farm animals, including farmed fish.

This could reduce the use of soy beans, for which vast areas of land are used, and overfishing of krill to feed farmed fish such as salmon.

The Cornish Circular Economies: Edible Insects project is funded by the European Regional Development Fund and Agritech Cornwall.

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Tackling the trillion dollar Alzheimer’s disease It’s almost impossible to conceive the complexity that lies ahead in the challenge to address Alzheimer’s disease. But, picture standing in front of an old mansion house, completely overgrown with ivy, trees, and shrubs. It’s imposing, three, four, five stories high, and the undergrowth is so dense that you can’t see beyond the front facade. You can peer through the dusty windows, but it’s very dark inside, and hard to make out anything. The front door, of course, is bolted shut. Now, imagine it’s your job to map out the entire house from where you stand; every room, doorway, corridor, staircase – and how they all interconnect. The challenge is seemingly impossible.

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ike the mansion house, Alzheimer’s disease is highly complex and poorly understood. Symptoms are no better defined than cognitive and functional impairment, which become more acute with disease progression; and the cause (other than in a few specific genetic cases) is broadly unknown. The leading theory is that Alzheimer’s results from the deposition of amyloid plaques and tau neurofibrillary tangles (misfolded and tangled proteins) in the brain, together with a loss of brain mass. None of this is definitive as many individuals that do have such features, never develop disease.

Genetic variants of the APOE gene can offer greater insight into the risk of developing Alzheimer’s. Indeed, the APOE E4 variant is recognised as the single most significant genetic risk factor for development of late onset disease. However, while 20-30% of people carry the APOE E4 variant, these individuals only account for up to 60% of all Alzheimer’s cases; ie at least 40% of patients do not carry APOE E4.1 We do know is that the complexity of Alzheimer’s stems from multiple risk factors based in genetics, lifestyle, age, and environment. As a result, there have been no new approved drug therapies since 2003; and until very recently clinical trial failure rates ran at 99.6%. Today over 50 million people worldwide are living with dementia, an umbrella definition covering more than 100 conditions that impair memory and cognition – of which Alzheimer’s accounts for 50-70%. Best estimates set this figure to double every 20 years. The resulting global economic and healthcare financial burden of dementia broke the $1tn mark in 2018, and is estimated to reach $2tn per year by 2030.2

THE CHALLENGE AND FIRST STEPS TO TACKLING ALZHEIMER’S Put simply, the challenge we face in treating Alzheimer’s is that we have incomplete information. Firstly, about the nature of the disease, what causes it and how it progresses; and secondly about the patient, and their risk of developing disease in a largely unknown disease pathway.

To date, Alzheimer’s – seen in patients as cognitive and functional impairment – has been defined by phenotypic symptoms, the deposition of amyloid plaques, loss of brain mass, plus the APOE gene variants that any individual may carry. As discussed, while these may be indicative of disease and the potential risk of developing disease, they have significant shortcomings.

Cytox is taking a far deeper look into the genetics behind Alzheimer’s and provides non-invasive, risk assessment and patient stratification tools for the disease through a technique called a Polygenic Risk Score (PRS). PRS can provide a probability of a disease trait arising, based on multiple genetic loci and their associated disease-causing weights. The technique is not unique to Alzheimer’s, indeed there is substantial research efforts in developing PRS approaches in coronary artery disease, type 2 diabetes, inflammatory bowel disease, breast cancer and glaucoma.

The Cytox approach to calculating a PRS in Alzheimer’s uses its genoSCORE™ and genoTOR™ products that can detect and interpret around 500,000 single nucleotide polymorphisms (SNPs) linked to the disease. These SNPs may be either causative of or protective against Alzheimer’s.

As these tests are based on genetics, they can be carried out at any age, and before disease symptoms arise. The output from genoSCORE™ and genoTOR™ provide a risk score for developing disease, and indications on the timing of onset.

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The age-old question remains however, “if there are no drugs to treat disease, how can knowing the risk and timing help, and does a patient want to know?” Interestingly, a recent UK report from Alzheimer’s Research UK, and the pharmaceutical company MSD, explored public attitudes towards diagnostics in Alzheimer’s. The report survey, based on interviews with over 2,000 adults, concluded that 74% of people said they would want to know if they had Alzheimer’s before symptoms develop. This broke down to 38% who would want to know 15 years ahead of symptoms, and 33% two years ahead of symptoms. 3 And there is good reasoning for this.

The ability to predict these two parameters – risk of disease and timing of onset – are paramount in the future management of Alzheimer’s. Early predictions – long before symptoms arise – allow for early interventions, which for now revolve around healthier lifestyle choices. These include improved diet and exercise, similar to those that negate cardiovascular disease and diabetes.

Secondly, and central to the development of new drugs, is the ability to identify patients at risk of developing disease, especially those with mild cognitive impairment (MCI) at risk of further substantial cognitive decline. The identification and recruitment of such patients to clinical trials increases the probability of observing the therapeutic efficacy of drugs being investigated. If efficacy can be shown, assuming it’s safe, there is a pathway to getting regulatory approval and treating patients.

OPENING THE BOLTED DOOR Despite the multi-trillion dollar societal burden that dementia and Alzheimer’s pose, with hundreds of millions of people anticipated to need treatment in the coming years, poor success rates in Alzheimer’s clinical trials have kept most pharma and biotech companies out of the field.

And while recent news from Biogen that it is planning to seek FDA approval for its anti-amyloid drug, aducanumab, will likely create a new hope to the field, far more clinical trials in Alzheimer’s disease are required before they are comparable to oncology – a disease in which major advances are coming through to patients. In 2015 there were 139 registered trials in Alzheimer’s vs 4,976 trials in cancer.

Having a greater understanding of, and the ability to interpret, the complex genetics behind Alzheimer’s is the first step to better characterising the disease. Furthermore, stratifying patients by their genetics is an essential step towards a more rational and targeted approach to drug development in the field. Cytox, through its polygenic risk score products – genoSCORE™ and genoTOR™ – is able to provide such insight.

And while this technology cannot provide all the answers from day one, it can unlock the door to the mansion house, provide the start of a floor plan and shine some light on where we should explore first.

References 1. JAMA (1997) 278, 1349 Farrer et al.

2. World Alzheimer’s Report 2015 www.alz.co.uk/research/ WorldAlzheimerReport2015.pdf 3. Detecting and Diagnosing Alzheimer’s Disease 2019 www.alzheimersresearchuk.org/wp-content/uploads/2019/12/1132267-PublicPerceptions-Report_v5.pdf

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| dementia |

Cytox is taking a far deeper look into the genetics behind Alzheimer’s and provides non-invasive, risk assessment and patient stratification tools for the disease through a technique called a Polygenic Risk Score (PRS). PRS can provide a probability of a disease trait arising, based on multiple genetic loci and their associated disease-causing weights. The Cytox approach to calculating a PRS in Alzheimer’s uses its genoSCORE™ and genoTOR™ products that can detect and interpret around 500,000 single nucleotide polymorphisms (SNPs) linked to the disease.

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Build-up of brain proteins affects genes in Alzheimer’s disease New research has shed fresh light on how the build-up of two proteins in the brain might affect the activity of genes involved in Alzheimer’s disease.

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esearchers at the University of Exeter worked in collaboration with Eli Lilly and Company to examine the brains of mice carrying mutations in the genes for the proteins amyloid and tau. The build-up of both proteins in specific regions of the brain is known to play a role in Alzheimer’s disease.

In a paper published today in Cell Reports, the researchers found evidence that the levels of gene activity changed dramatically as tau and amyloid accumulated in the brain. The team, funded by Alzheimer’s Research UK and Alzheimer’s Society, observed significant changes in the levels of genes involved in inflammation in the immune system, which became more active as tau levels increased.

The research also highlights new pathways potentially involved in the progression of Alzheimer’s disease, and adds weight to theories that brain inflammation is a key component in the build-up of tau.

First author Dr Isabel Castanho, of the University of Exeter, said: “Our results suggest that the genes which are disrupted through the build-up of tau and amyloid in the entorhinal cortex region of the brain influence the function of the immune response in the brain, which is known to be a key component of Alzheimer’s disease.”

The team analysed the build-up of each protein in the brain and the expression of genes associated with them as the mutant mice got older. They observed a build-up of both tau and amyloid, with these changes associated with widespread changes in gene expression – particularly in the case of tau. This is interesting because it suggests that the accumulation of tau might have more dramatic effects on gene regulation in the

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brain than amyloid. Furthermore, a number of the identified genes are known risk factors for Alzheimer’s disease, and overall the changes observed in mice mirror those seen in human Alzheimer’s disease brains.

Professor Jonathan Mill, of the University of Exeter Medical School, who led the project said: “Currently, no treatments are available that can change the course of Alzheimer’s disease. Understanding the interaction between genes and progression of the disease will help us identify new targets for treatment, which we hope will one day lead to drugs that can effectively treat this terrible disease.”

Dr Sara Imarisio, Head of Research at Alzheimer’s Research UK said: “Genetics plays an important role in the development diseases like Alzheimer’s and teasing apart the processes contributing to disease is crucial in the hunt for new breakthroughs, which will change lives. Future research capitalising on genetic findings like this is a top priority for dementia researchers around the world. It’s only thanks to the generosity of our supporters that Alzheimer’s Research UK is able to fund vital dementia research like this.”

Dr James Pickett, Head of Research at Alzheimer’s Society, said: “We’re proud to be funding research like this which plugs gaps in our knowledge about Alzheimer’s disease, and lays strong foundations for the development of new lifesaving treatments. Through research we will beat dementia. We owe it to the 850,000 people in the UK currently living with dementia to understand the condition better and find a cure.”

The full paper is entitled ‘Transcriptional signatures of tau and amyloid neuropathology’.

“Genetics plays an important role in the development diseases like Alzheimer’s and teasing apart the processes contributing to disease is crucial in the hunt for new breakthroughs, which will change lives.”

DR SARA IMARISIO, HEAD OF RESEARCH AT ALZHEIMER’S RESEARCH UK

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How the brain’s immune system could be harnessed to improve memory When it comes to memory, immune cells are known as the “bad cops” of the brain. But new research shows they could also be turned into “good cops” to power memory and learning.

Inflammation can send the brain’s immune cells into damaging hyperdrive, and this has been linked to neurodegenerative diseases that affect memory, like dementia.

In the new study, researchers at RMIT University found that these same immune cells – known as microglia – can also be activated to have the reverse effect.

When the microglia were altered in rats, their performance in simple memory tasks improved by up to 50%, rather than deteriorating.

While the effect was temporary, the discovery suggests these cells could be targeted in the development of new therapies designed to enhance memory formation, with the hope of preventing cognitive decline as people grow older.

Worldwide, around 50 million people have dementia, with nearly 10 million new cases each year. In Australia, dementia and ageing-related cognitive decline affect 9% of people aged over 65.

Chief Investigator and senior author, Associate Professor Sarah Spencer, said the unexpected results of the study expanded our understanding of memory formation and the role of neuroinflammation in memory loss.

“Cognitive decline is a big problem for our ageing population, and we currently have very few treatments to treat or prevent it,” Spencer said.

“Even in healthy adults, optimising how well we learn and remember can give us a substantial performance edge at work and socially.

“Our study has for the first time shown a link between changes in the immune cells of healthy brains and improved cognitive function.

“While it’s early days and a lot more research is needed, we hope our findings may lead to new therapies that can stimulate these immune cells to boost memory and keep our brains powering as we age.”

ACTIVATING MEMORY WITH ACTIVATED MICROGLIA In the study, published in Journal of Neuroinflammation, the researchers worked with a unique type of rat to test the effect of microglia on cognitive function.

The study looked how the rats performed memory tasks when the immune cells were present and compared this with their performance when almost all the microglia were knocked out.

A magnified image showing the regenerated microglia.

They have a similar shape to the “activated” shape that the brain’s immune cells have when dealing with inflammation.

Image: Alita Soch

L-R: Associate Professor Sarah Spencer and Dr Simone De Luca, RMIT University They found that removing almost all the microglia made no difference in memory tasks.

But when the microglia regenerated, this led to astounding results: researchers ran the same memory tests on the rats and they performed 25-50% better than normal rats.

Importantly, the regenerated microglia were a different shape - similar to the “activated” shape that these cells have when dealing with inflammation.

“We are still exploring what makes these cells different when they repopulate the brain, but their shape tells us they may be more active than usual, potentially making the neurons more effective to encourage better memory,” Spencer, an NHMRC Career Development Fellow at RMIT, said.

“The effect doesn’t last. As the microglia go back to their usual shape, memory performance also goes back to normal.

“The next stage in the research is closely investigating these regenerated microglia to better understand the mechanisms at work, with the aim of finding ways to turn the temporary memory boost into a long-lasting effect.”

Microglia-suppressing therapies are currently being tested in clinical trials in the US, as potential treatments for Multiple Sclerosis.

“With our new understanding of the role of microglia in memory, it may be possible in future to test the therapies originally designed for MS and assess their potential in improving cognitive function as well,” Spencer said.

Spencer is a leading researcher in the Neurodevelopment in Health and Disease program at RMIT, a multi-disciplinary research group in the School of Health and Biomedical Sciences established to identify the determinants of healthy brain development, and early origins of neurological disease.

‘Glial remodeling enhances short-term memory performance in Wistar rats’, with lead author Dr Simone de Luca, is published in Journal of Neuroinflammation

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POSTGRADUATE STUDY FOR LIFE SCIENCES GRADUATES WHERE NEXT WITH YOUR DEGREE? If you have studied a life science subject such as biomedical science, microbiology, genetics, anatomy or biology then the University of Birmingham may offer the perfect postgraduate programme to help you take your next step.

We offer a variety of programmes to suit your individual needs and interests, backed up by the academic expertise, facilities and influence of a global university. To find out more get in touch at one of our Open Days (either on campus or virtually).

At the University of Birmingham we offer a wide range of over 30 postgraduate programmes suitable for recent life science graduates including:

MASTERS PROGRAMMES n n n n n n n n n n n n n n

Bioinformatics Clinical Neuropsychiatry Clinical Trials Dental Materials Science Genomic Medicine Health Economics and Health Policy Health Research Methods Immunology and Immunotherapy Microbiology and Infection Molecular Biotechnology Physician Associate Public Health Toxicology Trauma Science

MASTER OF RESEARCH PROGRAMMES Cancer Sciences Clinical Health Research n Biomedical Research: Cardiovascular Sciences n Molecular and Cellular Biology n Molecular Mechanistic Toxicology

STAY IN TOUCH We offer several opportunities for you to find out more with campus-based Open Days, Virtual Open Days and of course, you can always email or call.

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We also offer a wide range of PhD programmes.

OPEN DAY

11 March 2020 Our Postgraduate Open Day will give you the best opportunity to hear firsthand from our current students and staff about our Masters and research opportunities. You can register online to keep up to date with event information.

VIRTUAL OPEN DAY If you can’t make it onto campus we also have a set of subject-specific Virtual Open days running in March. This will give the opportunity to chat online with the programme lead and watch videos about the programmes. You can register online to find out more.

To register for open days and for information about individual programme visit: www.birmingham.ac.uk/ pg-life-sciences

www.birmingham.ac.uk/pg-life-sciences

WHERE ARE THEY NOW? Our students are our best voice so we have included a few profiles below. To access more profiles of our postgraduate students please visit: www.birmingham.ac.uk/pg-life-sciences

MSC TRAUMA SCIENCE

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The opportunities given to me by far have been the best thing about the course. All the lecturers that have taught so far have come from different specialities and each have their own input into this course. They have offered me the opportunity to shadow them in the hospital and gain an exceptional experience.

Nirali is a MSc Trauma Science student who also holds a degree in Biomedical Science. She is keen on pursuing a degree in Medicine in the future. She currently works as a medical laboratory assistant in London and volunteers at many organisations.

MRES MOLECULAR AND CELLULAR BIOLOGY

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For me, I really wanted to gain more practical lab experience in biology after my undergraduate degree and see whether a career in research was for me. Doing an MRes has allowed me to work in two different labs throughout the academic year and gain a vast amount of experience in different areas of biology in terms of research topics and techniques.

Jagjeet is a full-time research student, who completed her MRes in Molecular and Cellular Biology at the University of Birmingham. She is currently studying towards a PhD in Immunology and Immunotherapy at Birmingham, having completed her undergraduate degree in Biological Sciences with Professional Placement at Aston University, which included an Erasmus placement in France.

To read Jagjeet’s full profile or ask her a question visit: pg.bham.ac.uk/mentor/j-kaurs/

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TABBY CAT OR TIGER? Medics need to be fleet of foot when it comes to determining whether they are dealing with something tame or wild, but the traditional route to identifying bacteria takes time. Now a team of Harvard researchers is coming to their aid in the fightback against drug resistance, HELEN COMPSON learns.

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ime is of the essence, of course. Faced with an unconfirmed illness, a medic on the frontline yet needs to choose a course of action.

And in terms of today’s desperate bid to halt the spectre of antibiotic resistance, the weight of responsibility has never been heavier.

But good news, help is on its way. A Harvard University research team is about to trial a new approach to analysis and prescription that one among its ranks says turns received wisdom on its head.

Actually, the way Bill Hanage, Associate Professor of Epidemiology, really put it was “we’ve taken a different approach to pretty much everybody else working in this field.

“The old school way of doing things was to take a sample, grow it on an agar plate, purify it, figure out it was exactly what you thought it was and then send it for testing all the way down the line, when what you want to know about is a specific pathogen and its antibiotic resistance determinants and to figure out the genome, so the approach is arse backwards.”

It takes time to get back the lab results that confirm diagnosis and precisely identify drug-resistant bacteria and all the while the illness can be galloping off into the distance.

Now, the Harvard team aims to arm medics with a new method, christened ‘genomic neighbour typing’, whereby the type of bacteria most likely at work in their patients is inferred within minutes of sequencing.

Simply put, metadata distils the identity of the bacteria’s closest relatives in a database of genomes.

Or as Bill Hanage explains it, “If you are walking in the jungle and there is huge feline with stripes, jaws and big teeth moving in the undergrowth near you and it starts growling, you don’t wait until you have sequenced its DNA before taking evasive action.

“All of the indicators are is that it’s a tiger and in the same way, if you look at all the information before you, you often find features that are correlated with drug resistance.”

All bacteria were not created equal – some were more prone to creating resistance than others. What genomic neighbour typing did was help medics make informed decisions about what they were dealing with.

“We know a lot about the world, we know what the resistance threats are,” said Bill. “What we have done is devise an approach whereby the doctor says, ‘hey, have I got a tiger in my sample?

“That’s a different question to ‘what are the antibiotic resistance characteristics of the sample?’

“You are just asking ‘have I got a tiger?’ You can send the samples to somebody else to count the stripes.”

Drug resistance is often described in apocalyptical terms: one of the biggest threats to human health which, by

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2050, could be claiming ten million lives a year due to the inability to treat infection. The lives of our children and grandchildren are at stake …

Bill, who employs a mix of theoretical and laboratory work to research the evolution and epidemiology of infectious disease, takes a more measured view. “You hear it said that drug resistance is getting progressively worse, but that is false,” he said. “It is more complicated than that.

“Sometimes it does seem to be getting worse, but sometimes it appears to be getting better and it’s not clear what the factors are that determine that.

“However, what is true is the chance of someone you care about dying from drug-resistance infection is higher today.”

And that was a huge source of concern all over the world, particularly in places already facing a spectrum of increasingly untreatable infections. “It is a big deal,” he said.

“The Bill and Melinda Gates Foundation has given funding to develop research.

“As a doctor, you are seeing people fall ill with infections you used to be able to treat and now you cannot.

“Sometimes those people die or they are in hospital longer, where they are at risk of other complications and taking up beds.”

In helping medics prescribe more precisely and efficiently, the genomic neighbour typing method will reduce the reliance on broad-spectrum antibiotics.

“When a doctor sees a patient, initially they know nothing about what is causing the disease,” he said. “They probably know that what they are seeing is a urinary tract infection, judging from the symptoms presenting, but they don’t know the cause.

“So when it comes to prescribing antibiotics, that is based on previous experience and a best guess.”

While broad spectrum antibiotics, so called because they cover a lot of the bases, are a reliable fall-back, their usage produces tremendous selective pressure not only on the potentially dangerous pathogen, but also on all the other bacteria in the body to evolve resistance, because they are all being targeted.

What the new method does is help the doctor on the hospital floor to recognise, ‘this is the same condition that was affecting patient ‘x’ we treated successfully last week using this drug’.

Bill said: “This could enable doctors to use narrow spectrum antibiotics, the specifically-targeted silver bullets, with the same confidence they currently use broad-spectrum antibiotics.

“It will allow us to take some old drugs that have been abandoned as too narrow spectrum back off the shelf and start using them again.”

Thereby bolstering the armoury being used in the battle with drug resistance.

“If you are walking in the jungle and there is huge feline with stripes, jaws and big teeth moving in the undergrowth near you and it starts growling, you don’t wait until you have sequenced its DNA before taking evasive action.”

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Bill Hanage Associate Professor of Epidemiology, Harvard University

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Artificial intelligence yields new antibiotic A deep-learning model identifies a powerful new drug that can kill many species of antibiotic-resistant bacteria.

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sing a machine-learning algorithm, MIT researchers have identified a powerful new antibiotic compound.

In laboratory tests, the drug killed many of the world’s most problematic disease-causing bacteria, including some strains that are resistant to all known antibiotics. It also cleared infections in two different mouse models.

The computer model, which can screen more than a hundred million chemical compounds in a matter of days, is designed to pick out potential antibiotics that kill bacteria using different mechanisms than those of existing drugs.

“We wanted to develop a platform that would allow us to harness the power of artificial intelligence to usher in a new age of antibiotic drug discovery,” says James Collins, the Termeer Professor of Medical Engineering and Science in MIT’s Institute for Medical Engineering and Science (IMES) and Department of Biological Engineering. “Our approach revealed this amazing molecule which is arguably one of the more powerful antibiotics that has been discovered.”

In their new study, the researchers also identified several other promising antibiotic candidates, which they plan to test further. They believe the model could also be used to design new drugs, based on what it has learned about chemical structures that enable drugs to kill bacteria.

“The machine learning model can explore, in silico, large chemical spaces that can be prohibitively expensive for traditional experimental approaches,” says Regina Barzilay, the Delta Electronics Professor of Electrical Engineering and Computer Science in MIT’s Computer Science and Artificial Intelligence Laboratory (CSAIL).

Barzilay and Collins, who are faculty co-leads for MIT’s Abdul Latif Jameel Clinic for Machine Learning in Health, are the senior authors of the study, which appears in Cell.

The first author of the paper is Jonathan Stokes, a postdoc at MIT and the Broad Institute of MIT and Harvard.

A NEW PIPELINE Over the past few decades, very few new antibiotics have been developed, and most of those newly approved antibiotics are slightly different variants of existing drugs.

Current methods for screening new antibiotics are often prohibitively costly, require a significant time investment, and are usually limited to a narrow spectrum of chemical diversity.

“We’re facing a growing crisis around antibiotic resistance, and this situation is being generated by both an increasing number of pathogens becoming resistant to existing antibiotics, and an anemic pipeline in the biotech and pharmaceutical industries for new antibiotics,” Collins says.

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To try to find completely novel compounds, he teamed up with Barzilay, Professor Tommi Jaakkola, and their students Kevin Yang, Kyle Swanson, and Wengong Jin, who have previously developed machine-learning computer models that can be trained to analyze the molecular structures of compounds and correlate them with particular traits, such as the ability to kill bacteria.

The idea of using predictive computer models for “in silico” screening is not new, but until now, these models were not sufficiently accurate to transform drug discovery. Previously, molecules were represented as vectors reflecting the presence or absence of certain chemical groups. However, the new neural networks can learn these representations automatically, mapping molecules into continuous vectors which are subsequently used to predict their properties.

In this case, the researchers designed their model to look for chemical features that make molecules effective at killing E. coli. To do so, they trained the model on about 2,500 molecules, including about 1,700 FDA-approved drugs and a set of 800 natural products with diverse structures and a wide range of bioactivities.

Once the model was trained, the researchers tested it on the Broad Institute’s Drug Repurposing Hub, a library of about 6,000 compounds. The model picked out one molecule that was predicted to have strong antibacterial activity and had a chemical structure different from any existing antibiotics.

Using a different machine-learning model, the researchers also showed that this molecule would likely have low toxicity to human cells.

This molecule, which the researchers decided to call halicin, after the fictional artificial intelligence system from “2001: A Space Odyssey,” has been previously investigated as possible diabetes drug. The researchers tested it against dozens of bacterial strains isolated from patients and grown in lab dishes, and found that it was able to kill many that are resistant to treatment, including Clostridium difficile, Acinetobacter baumannii, and Mycobacterium tuberculosis.

The drug worked against every species that they tested, with the exception of Pseudomonas aeruginosa, a difficult-totreat lung pathogen.

To test halicin’s effectiveness in living animals, the researchers used it to treat mice infected with A. baumannii, a bacterium that has infected many U.S. soldiers stationed in Iraq and Afghanistan. The strain of A. baumannii that they used is resistant to all known antibiotics, but application of a halicin-containing ointment completely cleared the infections within 24 hours.

Preliminary studies suggest that halicin kills bacteria by disrupting their ability to maintain an electrochemical

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gradient across their cell membranes. This gradient is necessary, among other functions, to produce ATP (molecules that cells use to store energy), so if the gradient breaks down, the cells die. This type of killing mechanism could be difficult for bacteria to develop resistance to, the researchers say.

“When you’re dealing with a molecule that likely associates with membrane components, a cell can’t necessarily acquire a single mutation or a couple of mutations to change the chemistry of the outer membrane. Mutations like that tend to be far more complex to acquire evolutionarily,” Stokes says.

In this study, the researchers found that E. coli did not develop any resistance to halicin during a 30-day treatment period. In contrast, the bacteria started to develop resistance to the antibiotic ciprofloxacin within one to three days, and after 30 days, the bacteria were about 200 times more resistant to ciprofloxacin than they were at the beginning of the experiment.

The researchers plan to pursue further studies of halicin, working with a pharmaceutical company or nonprofit organization, in hopes of developing it for use in humans.

OPTIMIZED MOLECULES After identifying halicin, the researchers also used their model to screen more than 100 million molecules selected from the ZINC15 database, an online collection of about 1.5 billion chemical compounds. This screen, which took only

three days, identified 23 candidates that were structurally dissimilar from existing antibiotics and predicted to be nontoxic to human cells.

In laboratory tests against five species of bacteria, the researchers found that eight of the molecules showed antibacterial activity, and two were particularly powerful.

The researchers now plan to test these molecules further, and also to screen more of the ZINC15 database.

The researchers also plan to use their model to design new antibiotics and to optimize existing molecules. For example, they could train the model to add features that would make a particular antibiotic target only certain bacteria, preventing it from killing beneficial bacteria in a patient’s digestive tract.

The research was funded by the Abdul Latif Jameel Clinic for Machine Learning in Health, the Defense Threat Reduction Agency, the Broad Institute, the DARPA Make-It Program, the Canadian Institutes of Health Research, the Canadian Foundation for Innovation, the Canada Research Chairs Program, the Banting Fellowships Program, the Human Frontier Science Program, the Pershing Square Foundation, the Swiss National Science Foundation, a National Institutes of Health Early Investigator Award, the National Science Foundation Graduate Research Fellowship Program, and a gift from Anita and Josh Bekenstein.

“We wanted to develop a platform that would allow us to harness the power of artificial intelligence to usher in a new age of antibiotic drug discovery. Our approach revealed this amazing molecule which is arguably one of the more powerful antibiotics that has been discovered.”

JAMES COLLINS, THE TERMEER PROFESSOR OF MEDICAL ENGINEERING AND SCIENCE IN MIT’S INSTITUTE FOR MEDICAL ENGINEERING AND SCIENCE (IMES) AND DEPARTMENT OF BIOLOGICAL ENGINEERING.

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Will 2020 be the Year You Make the Most of Innovation Tax Reliefs It’s the start of a new decade and with that comes the chance to have a fresh look at everything that is happening in your business.

It is likely to be the most active decade for innovation that the world has ever known, with continuing advances in artificial intelligence and green technology and solutions to save the world, given even more focus by the competition announced over the New Year by the Duke of Cambridge with Sir David Attenborough. Innovation is surely going to be omnipresent!

You must also ask yourself the question, “Am I paying the right amount of tax?” When it comes to your corporate tax bill, which ultimately affects your profitability as much, if not more than most costs in your business, the question you should be asking is “Am I making the most of my available Tax Reliefs?”

Generally, Tax Reliefs are a legitimate way of reducing a company’s tax liability. Government have legislated tax reliefs for innovation, open to companies across all industries.

RESEARCH AND DEVELOPMENT TAX RELIEF The definition of Research and Development for Tax Relief is “a company must be undertaking a project to seek an advance in science or technology through the resolution of scientific or technological uncertainties.

The advance being sought must constitute an advance in the overall knowledge or capability in a field of science or technology, not a company’s own state of knowledge or capability alone.” Finally, a competent professional operating in the field mustn’t be able to readily deduce a solution.

people and have a turnover of less than €100m or a gross asset value on their Balance Sheet of less €86m, who are performing research and development at their own financial risk.

If you don’t meet these criteria or you are performing paid R&D for another company or you’ve received a grant or subsidy for your R&D then you can claim under RDEC. The SME Scheme will deliver tax relief for a profitable company worth up to 24.7% of the eligible spend, a loss making company can surrender their loss up to a value of 230% of the R&D spend for a repayable R&D Tax Credit, which can be worth up to 33.35% of the eligible spend.

The RDEC Scheme is significantly less rewarding at around 9.72% of the eligible spend, but still quite a significant amount of cash.

PATENT BOX

There are two R&D Tax Relief schemes, the SME Scheme and RDEC Scheme.

If your company has actively participated in the development of a product that has been granted a UK or EU patent and you will be actively selling the patented item or a product with that patented item embedded within it, then you will be able to claim Patent Box. The patented item doesn’t have to be your own product, it could be someone else’s but you have to have been involved in the research and development of that product and more importantly you have to have an exclusive licence to sell that product within a “National” market.

The SME Scheme is for small and mediumsized entities who employ less than 500

The tax relief for a Patent Box claim is an additional deduction from the company’s

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profits that equates to a reduction in the tax charge on the profits derived from selling that product from 19% to 10%. The profits derived is a complex calculation and isn’t just a case of tallying up the sales and deducting the cost of sales.

The one thing to be wary of with a Patent box claim is that products with a low volume and or a low margin might well create a loss for Patent Box (which you really don’t want), it’s always best to calculate the value of a potential claim first.You can’t pick and choose your patents, it’s all or nothing!

DESIGNED FOR INNOVATION Both Patent Box and R&D Tax Relief have been designed to encourage businesses to seek Innovative ways to improve their existing products or processes or to develop completely new ones. R&D Tax Relief will soon be celebrating its 20th birthday and yet it remains widely underclaimed by businesses across all industries.

Both are also fairly complex and ideally you should seek expert advice that might be outside of your current accountant and tax adviser, if you’ve always been doing it, they are unlikely to tell you that you might qualify after 20 years! www.coodentaxconsulting.co.uk

| BIOSCIENCE TODAY |

| news |

Betrayed by bile: bile acids help norovirus sneak into cells A new study led by researchers at Baylor College of Medicine and published in the Proceedings of the National Academy of Sciences reveals that human noroviruses, the leading viral cause of foodborne illness and acute diarrhea around the world, infect cells of the small intestine by piggybacking on a normal cellular process called endocytosis that cells use to acquire materials from their environment.

The study found that two compounds present in bile – bile acids and the fat ceramide – are necessary for successful viral infection of a laboratory model of the human small intestine. In addition, the researchers report for the first time that bile acids also stimulate endocytosis in the small intestine. The findings support further exploration of the possibility of reducing norovirus infection by modulating the levels of bile acids and/or ceramide.

“Human noroviruses invade cells of the small intestine where they replicate and cause gastrointestinal problems,” said co-first author Victoria R. Tenge, graduate student of molecular virology and microbiology in Dr. Mary Estes’s laboratory.

“Previous work from our lab showed that certain strains of norovirus required bile, a yellowish fluid produced by the liver that helps digest fats in the small intestine. In the current study, we investigated which bile components were involved in promoting norovirus infection.”

“Interestingly, we also discovered that bile acids stimulated the process of endocytosis in mini-guts. Our findings led us to propose that as bile acids activate endocytosis, they create a stage that norovirus takes advantage of by riding along with it to enter the cells and subsequently replicate, causing disease,” said corresponding author, Dr. Mary K. Estes, Cullen Foundation Endowed Professor Chair of Human and Molecular Virology at Baylor College of Medicine and emeritus founding director of the Texas Medical Center Digestive Diseases Center. “Bile acid-induced endocytosis in the small intestine was not previously appreciated.”

“This strategy works well for a food-borne virus,” said co-first author Dr. Kosuke Murakami, who was working in the Estes lab during most of this project. He is currently at the National Institute of Infectious Diseases in Tokyo.

“As people ingest food, the body’s normal response is to secrete bile into the small intestine. Noroviruses contaminating food piggyback on this natural bodily response to invade cells in the small intestine, replicate and cause disease.”

The researchers worked with human enteroids, a laboratory model of human intestinal cells that retains properties of the small intestine and is physiologically active.

“Mini-guts, as we call them, closely represent actual small intestine tissue, and, importantly, they support norovirus growth, allowing researchers to study how this virus causes disease,” said co-first author Dr. Umesh Karandikar, a research scientist in the Estes lab.

CREATING A STAGE THAT FAVORS VIRAL INFECTION The researchers discovered that bile acids and ceramide in bile were necessary for viral infection.

Working with mini-guts not only showed new insights into how norovirus causes disease, but also illuminated details about the basic biological process of endocytosis in the small intestine that had not been reported before.

“Our findings suggest the possibility that modulating the amount of bile acids and/or ceramide could help reduce norovirus infection,” Tenge said.

“This strategy might be particularly helpful to people who have norovirus infections for months, even years,” Karandikar said.

“Previous work from our lab showed that certain strains of norovirus required bile, a yellowish fluid produced by the liver that helps digest fats in the small intestine. In the current study, we investigated which bile components were involved in promoting norovirus infection.”

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| news |

| BIOSCIENCE TODAY |

Newcastle based company addresses key challenge to the success of lab-grown meat With a predicted world population reaching just short of 10 billion by 2050 (3 billion more than there were in 2010), developing efficient, environmentally friendly and affordable food production technologies becomes a real challenge. Additionally, the livestock sector is already responsible for 14.5% of greenhouse gas (GHG) emissions, and uses 30% and 8% of the Earth’s terrain and freshwater respectively. There are also growing concerns regarding food safety and contaminants present in our meat e.g. antibiotics, plastics, mercury etc. It is estimated that the global meat demand will increase by 73% by 2050, and therefore producing meat independently from livestock can be seen as a feasible and sustainable alternative. There are also growing concerns regarding food safety and contaminants present in our meat e.g. anti-biotics, plastics, mercury etc.

Cultured meat, which is a form of cellular agriculture, is meat produced by in vitro cultivation of animal cells, instead of from slaughtered animals. Although this has been the subject of research since the 1970s, many commentators now believe cultured meat will soon enter the global processed meat industry which is projected to grow from $714 billion in 2016 to $1.5 trillion by 2022.

The rationale and business case of cultured meat mainly relies in the following reasons: i) it is more environmentally friendly; ii) It allows slaughter free meat consumption and iii) The meat contains fewer contaminants Currently, cultured meat is produced by growing cells on a surface until no free space remains, at which point all the cells are detached and collected. The process is then repeated to produce the next batch. CellulaREvolution Ltd is developing a continuous approach by coating the surface with a functional coating (lipopeptides) before seeding with cells (1). After the cells grow, they “self-detach� from the lipopeptide coating, allowing other immature cells to take their place, so there is no need to chemically or enzymatically detach the whole batch. This novel approach facilitates a continuous or unremitting production of adherent cells without the need to reset the system i.e. not a batch process.

However, despite the great promise of cultured meat, scaling up its production is a considerable and costly hurdle for these companies. A small meat patty will contain about 10 billion adherent cells and using traditional batch processes could take a single 5000L bioreactor 1 month to produce.

The technology being developed by CellulaREvolution could reduce the time down to one week whilst requiring significantly less media and space.

This in turn means that cultured meat companies using our technology will be able to solve three of the main issues currently present in the industry (i. Removal of serum from the production process, ii. Scale-up so that production capacity can meet expected demand, iii) Reduce cultured meat cost to become comparable to conventional meat products.

CellulaRevolution is still a nascent company, only to have become fully incorporated in July 2019. Since then, the company founded by Martina Miotto (CSO), Che Connon (CTO) and Leo Groenewegen (CEO), has managed to grow to a team of seven.

The short-term goals of the company are to use the prototype of its continuous bioreactor to start making first sales to cultured meat companies, many of whom we are currently in close collaboration with. The company is also planning a funding round mid-late 2020 which will allow the company to really gear up for uninhibited growth!

CellulaRevolution is also starting to become a real thought leader in the field of cultured meat and cell therapy. As such CellulaREvolution CEO, Leo Groenewegen has been invited as an expert speaker at two upcoming leading industry events (Industrializing Cell Based Meats and Advanced Therapies Congress and Expo) and soon both Martina Miotto and Leo Groenewegen will make their appearance on the Cultured Meat and Future Food Podcast, which is the leading podcast on cultured meat.

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| BIOSCIENCE TODAY |

| intellectual property |

Shanks v Unilever – An opening of the claim floodgates?

At the end of last year Professor Shanks was awarded £2 million for an invention relating to a glucose sensor made while employed working for Unilever. What does this mean for employee inventors and their employers?

Varuni Paranavitane

IP Solicitor, AA Thornton

BACKGROUND In 2006 Professor Shanks claimed compensation under s40 of the Patents Act on the basis that an invention he made as an employee was of outstanding benefit to his employer and that he was entitled to a ‘fair share’ of that benefit.

The Hearing Officer rejected the claim on the basis that his contribution fell short of being outstanding. This was appealed to the High Court, the Court of Appeal and finally the Supreme Court which decided in Professor Shank’s favour.

THE FACTS Professor Shanks was employed by a wholly owned subsidiary of Unilever PLC (‘Unilever’), which carried out research for the Unilever group and was not a trading company.

He was interested in bio-sensors for monitoring glucose in diabetics and built a prototype of his invention using his daughter’s toy microscope kit.

In 1984 Unilever filed a UK patent application, and subsequently filed world-wide applications, for the invention and named Professor Shanks as an inventor.

At the time, the type of technology covered by the patent was highly sought after and Unilever granted 7 licences of the Shanks patents for a revenue of £19.55 million.

In 2001 the Shanks patents and associated business were sold for £5 million. Therefore, Unilever’s earnings from the Shanks patents, was around £24 million.

THE DECISION The Supreme Court had to determine whether the Hearing Officer applied the correct principles to assess ‘outstanding benefit to an employer’ and also whether the ‘fair share’ of an outstanding benefit was assessed correctly.

In making the assessment of whether the patent was an outstanding benefit, Lord Kitchin looked at the Patents Act which set out that the court must regard the ‘size and nature of the employer’s undertaking’. Here the employer is a company that sits within the Unilever group.

Lord Kitchin held that “the focus of the inquiry into whether any one of those patents is of outstanding benefit to the company must be the extent of the benefit of that patent to the group and how that compares with the benefits derived by the group from other patents for inventions arising from research carried out by that company’” It is well known that Unilever makes a variety of products from Vienetta ice cream to deodorants and generates billions of pounds in sales, and hundreds of millions of pounds in profits, over the life of patents related to the products. In considering the relevance of the size and

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nature of an undertaking to assess outstanding benefit, Lord Kitchin held the following factors were relevant: whether the benefit would normally have been expected to arise from the duties for which the employee was paid; whether the benefit was arrived at without any risk to the business; whether the benefit represents an ‘extraordinarily high rate of return’; and whether it may have been the opportunity to develop a new line of business or to engage in unforeseen licensing opportunities.

Lord Kitchin held that the Hearing Officer was incorrect on a number points when considering whether the benefit was outstanding, including that there was no justification to simply weigh the sums Unilever generated from the Shanks patents against the size of its turnover and overall profitability. Lord Kitchin held that the Shanks patents were of outstanding benefit to the employer.

Lord Kitchin agreed that the Hearing Officer’s approach to arriving at figure of 5% of the total earnings was a ‘fair share’ and awarded Professor Shanks £2 million. This comprised the 5% of £24m (£1.2m) plus a sum of £0.8m to take into account of inflation.

FLOODGATES? It is unlikely that this decision will open the floodgates to successful employee inventor claims in the pharmaceutical industry as the facts are very specific, but it is reasonable to think that we might see more claims being considered in view of this success. Employers may be able to reduce the risks of a successful claim by adopting a robust inventor reward scheme so that inventors are appropriately rewarded early on.

If you have queries regarding this topic, or other medical device or pharmaceutical matters, please contact Varuni Paranavitane at vxp@aathornton.com or visit our website www.aathornton.com

| intellectual property |

| BIOSCIENCE TODAY |

Are your innovations protected?

Innovation is something that defines the biosciences sector.

The UK biotechnology and medical industries are among some of the most progressive in the world with billions invested annually on creating industry-leading drugs, techniques, therapies, and technology which transcend expectation.

Intellectual property and innovation are inextricably linked.

When you patent a product or other technology, you unlock the commercial potential of a ground-breaking innovation.

But without safeguarding the rights to your innovations through an effective intellectual property strategy, your product or technology could be copied, and others could take advantage of your investment.

Wynne-Jones IP partner Jim Robertson said protecting products and technologies in this field was “crucial” in order to safeguard the future of innovation and research.

He said: “Nowhere is an efficient and targeted plan more productive than in the biotech industry, particularly in protecting the rights of medical researchers and firms involved in developing the latest industry-leading drugs, therapies, medical devices and related technologies.

“These transformative creations not only have an intellectual value, which could enhance the care of millions of people across the world, but also a commercial value, which is realised when the products and technologies are used and taken to market.”

However, the whole area of IP can be a confusing minefield for innovators because it is presided over by a niche legal profession, it’s a specialised business area and, by its very nature, intangible.

Jim continues: “Every day we meet business leaders, even those from large, innovation-rich companies, who are confused about IP. We regularly hear them say, “What is IP?” or “How do we manage IP? How can we make IP contribute to the bottom line?” or “How much money should I spend on it?”.

“To help demystify IP and bring to life how a robust IP strategy can not only protect but grow innovative companies within the sector, we’re sharing how our work is supporting a company that develops and commercialises products to improve the safety, efficiency and outcomes of advanced surgical procedures.”

ALESI SURGICAL Alesi Surgical is a company that has developed Ultravision™ - a new and innovative product that clears surgical smoke from a surgeon’s view during laparoscopic surgery and prevents its escape into the operating theatre.

WHY THEY NEEDED IP PROTECTION? Ultravision™ is based on an electrostatic precipitation technique, which is unique to Alesi, and is highly effective at removing airborne particles.

Due to the innovative nature of the technique, Alesi engaged Wynne-Jones IP to help them protect their product to ensure the concept has commercial longevity.

For Alesi, like many other companies in the life sciences and technology sector, patent protection helps create a commercial niche for Ultravision™ which is useful when it comes to securing important funding for the company’s continuing research and development, in addition to the

principal right which enables Alesi to prevent unauthorised exploitation of the invention.

HOW WYNNE-JONES IP HELPED? Wynne-Jones IP identified the core technology and techniques required to exploit the benefits of the invention and sought to protect this technology. We submitted several patent applications to protect various aspects of the technology, including a patent application for the generic concept, another for a compact handheld embodiment, and an application directed to the electrical circuitry utilised by the technology.

As patents are territorial, we also worked with Alesi to help them identify the key territories where they should look to protect their technology and thus file respective patent applications. We have long established and trusted relations with a network of associates around the globe, whom we use when filing patent applications overseas. It is important to exploit the local knowledge of our associates, since different patent jurisdictions have their own nuances, which must be considered when filing the respective application, in order to optimise the protection achievable in those jurisdictions.

WHAT HAS IT MEANT FOR ALESI SURGICAL? The patent applications filed by Wynne-Jones IP, which were directed to the generic concept of Ultravision™, have now been granted in the majority of countries and these patents can remain in force for up to 20 years, provided so-called renewal fees are paid to the national patent offices.

Wynne-Jones IP will continue to file patent applications for Alesi as there is no upper limit to the number of patent applications which can be filed by one company. However, it is important to remember that once a patent application has been published, it can be used as “prior art” against any subsequent patent applications, including those filed by the same company.

In addition, any prior disclosure of an invention may count as “prior art” against any patent application you decide to file for that invention, so you should keep your inventions secret until you have filed the respective patent application.

As attorneys for Alesi, we regularly have meetings and tailor the patent protection to align with their current business direction, which may change due to research and development. Patents are there to protect their commercial niche, so it is important to continue submitting applications for any developments in the technologies to ensure Alesi has commercial longevity.

IN CONCLUSION… It is imperative that the biosciences industry recognises the importance of adopting effective intellectual property strategies, which can evolve with the development of worldleading products. Partnering up with your IP attorneys can make a huge difference.

Our commercially focussed attorneys are experienced at developing IP strategies which are linked to business goals.

If you’re interested in seeing how your business could benefit from a robust IP strategy or think your IP could work harder for your business, we’re happy to arrange a noobligation initial consultation. www.wynne-jones.com

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Your team for Life Sciences IP Is Life Sciences your field?

When you need help with intellectual property rights, remember that we’ve been active in this field for decades.

Whether you’re a lone inventor, SME or large corporation, you must identify and protect your Crown Jewels®. These are the core technologies, inventions or processes that are critical to your business strategy.

We will work with you to fully understand the commercial and strategic needs of your business and take away the hassle and worry of IP.

We know our stuff in: Bio-sensors | Diagnostics | Assays | Pharmaceuticals and Drug Synthesis | Small Molecules | Plant Breeders’ Rights | Cosmetics | Supplementary Protection Certificates | Vaccines | Biochemistry | Microbiology | Pharmacology | Biocides | Healthcare Sciences | Proteomics | Biophysics | Veterinary Medicines | Medical Devices

What’s more we know our stuff in: Strategic IP management | Setting IP budgets | IP asset management | Funding for IP

What are you waiting for?

Let’s talk Life Sciences.

Jim Robertson, Life Sciences Team Leader T: 01242 267 600 E: jim.robertson@wynne-jones.com W: www.wynne-jones.com

| gene therapy |

| BIOSCIENCE TODAY |

New Cell and Gene Therapy Catapult CEO brings continuity and ambition Matthew Durdy appointed to CEO role as the CGT Catapult prepares to accelerate innovation, growth and productivity, where needed in the UK. The Board of the Cell and Gene Therapy Catapult (CGT Catapult), a global leader in the field of advanced therapies, announced today that its new Chief Executive Officer will be Matthew Durdy, who is currently the Chief Business Officer of the organisation. The appointment will be effective from the beginning of April 2020. This comes after a formal external and internal recruitment process that was initiated after the announcement last October that Keith Thompson, the founding CEO, would be retiring in the spring of 2020.

The Board advertised for applicants who had deep sector experience; could inspire the confidence of the CGT Catapult’s diverse stakeholders; took a perspective of the industry as a global business; were strategic thinkers with a demonstrated track record of relationship building and negotiation; and, had a strong track record of leadership and financial management.

ABOUT MATTHEW DURDY

The appointment comes as the cell and gene therapy focussed organisation employs nearly 250 experts orientated around three key areas: manufacturing and supply chain; industrialisation and new technology development; and, global scale clinical adoption practices and product design. The core strategy will continue, and the organisation is prepared for further expansion of the industry and successfully meeting the increasing demands for innovation to drive growth and productivity.

Part of the 2012 team that created the CGT Catapult, he is also an Executive Director. As Chief Business Officer he has been responsible for strategy; and finding, funding and transacting the business of the CGT Catapult. He is credited with the design and implementation of the commercial model for the highly successful CGT Catapult manufacturing centre and being a global champion for the early integration of healthcare economics and reimbursement expertise into decision-making and clinical product design.

Matthew Durdy

Supporting progress of cell and gene therapy industrialisation with new aseptic manufacturing course With cell and gene therapies moving towards commercialisation and employment in this space predicted to reach over 6,000 jobs by 2024, this initiative aims to provide targeted training which will support this growth and address the accelerating demand for skills in the sector. The bespoke course will offer training on aseptic advanced therapy manufacturing in line with industry standards.

The Cell and Gene Therapy Catapult (CGT Catapult) and the University of Hertfordshire today announced the launch of a new course specifically addressing the foreseeable skills gap in the manufacture of cell and gene therapies as they progress towards manufacturing at scale. Developed in a collaboration between the two organisations, this three-day course will provide theoretical and practical training on the aseptic manufacturing of cell and gene therapies in line with European regulatory guidance for good manufacturing practice (GMP).

The cell and gene therapy industry in the UK currently supports over 3,000 jobs, a six-fold increase since 2012, and employment in the sector is set to more than double by 2024 as more therapies progress towards

commercialisation. Manufacturing and bioprocessing roles in particular have tripled in the past two years alone, with scientists operating in the 26 cell and gene therapy manufacturing facilities throughout the UK. Cell and gene therapies are transformative and potentially curative medicines, and it is vital that manufacturing processes are safe and efficient whilst preserving the effectiveness of these living medicines.

The new training programme is designed for staff working in cell and gene therapy manufacturing.

Delegates will benefit from experience in state-ofthe-art facilities and will be awarded a University of Hertfordshire accredited certificate upon successful completion of the training, contingent on assessments of their knowledge, understanding and practical skills.

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| BIOSCIENCE TODAY |

| gene therapy |

UK accounts for over 12% of global cell and gene therapy clinical trials The UK and the NHS are providing the right environment and infrastructure to allow innovative cell and gene therapies to reach patients. International companies recognise the appeal of the UK cell and gene therapy ecosystem and are sponsoring the majority of the UK commercial clinical trials which account for 77% of the total 127 ongoing trials.

The Cell and Gene Therapy Catapult (CGT Catapult) released their 2019 UK advanced therapies medicinal products (ATMPs) clinical trials database showing that the 127 ongoing trials represent a ~45% increase compared to 2018, and account for 12% of the total global cell and gene therapy clinical studies.

The NHS and UK ecosystem are providing the right platforms to allow innovative therapies to progress through to the clinic in ever increasing numbers. Cell and gene therapies require novel approaches, systems and infrastructure to enable the delivery of these life changing, living medicines to patients. The favourable UK environment is being recognised internationally with the majority of commercially sponsored trials being backed by international organisations.

Cell and gene therapies continue to progress towards large scale commercialisation to add to the therapies already approved for use. The database shows that 77% of UK cell and gene therapy trials are now sponsored by commercial organisations compared to only 25% in 2013. This number reflects the continuous investment that companies are making in cell and gene therapies, and the transformative effects that these therapies are proving to have on patients’ lives.

The main indication for cell and gene therapies clinical trials remains oncology (39%) followed by ophthalmology (13%) and haematology (12%).

Orgenesis Announces Collaboration with The John Hopkins University for the Development and Processing of Cell and Gene Based Clinical Therapeutics Orgenesis Inc., a provider of point-of-care cell and gene therapy development, processing and treatment solutions (“POCare”), today announced that it has entered into a collaboration agreement with the John Hopkins University (“JHU”) to utilize Orgenesis’ POCare platform to develop and supply a variety of cell and gene therapies and technologies, including cell-based immunotherapy technologies.

Vered Caplan, CEO of Orgenesis, stated, “JHU has unparalleled capabilities in the cell and gene therapy sector. Our POCare platform is designed to provide unique

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cell and gene therapy solutions in a cost effective, high quality and scalable manner, using closed systems and other advanced cell processing technologies at the point of care. We look forward to utilizing our POCare platform to support JHU’s growing development and processing needs in order to advance and accelerate cell and gene based clinical therapeutic research. We believe this collaboration with JHU, a clear leader in the field of cell and gene therapy, further validates the significant value proposition of our POCare platform. Moreover, this is the third major agreement signed by an international institution in recent months to utilize Orgenesis’ POCare solutions.”

| genome reprogramming |

| BIOSCIENCE TODAY |

Hyperactive FOXA1 reprograms endocrine-resistant breast cancer to become metastatic A team led by researchers at Baylor College of Medicine and Harvard Medical School has unveiled a novel mechanism that helps explain how endocrine-resistant breast cancer acquires metastatic behavior, opening the possibility of new therapeutic strategies.

Published in the Proceedings of the National Academy of Sciences, the study shows that hyperactive FOXA1 signaling, which previously was reported in endocrineresistant metastatic breast cancer, triggers genome-wide reprogramming that results in enhanced resistance to treatment and metastatic behaviors.

The researchers also identified HIF-2a as a key mediator of FOXA1-directed reprogramming and showed that an inhibitor of HIF-2a, currently under clinical development for treatment of advanced renal cell carcinoma and recurrent glioblastoma, can effectively reduce migration and invasion of endocrine-resistant breast cancer cells expressing high FOXA1 activity.

“About 75 percent of breast cancers have estrogen receptors, hence they are called estrogen receptor positive (ER+).

Original ER+ breast cancer cells depend on estrogen to grow, and therapies that make the estrogen unavailable to cells, called hormone therapies, can result in long-term remission in some patients. Tamoxifen, one of several types of hormone therapy, works by binding to and blocking the estrogen receptor on cancer cells,” said co-corresponding author Dr. Rachel Schiff, associate professor of medicine and the Lester and Sue Smith Breast Center at Baylor.

However, most patients with metastatic disease, including those whose tumors responded initially to hormone therapy, eventually relapse and die due to the tumors’ acquired resistance to hormone therapy.

In previous work, Schiff and her colleagues discovered that tumor cells resistant to hormone therapies make more FOXA1 than susceptible cells, and this abundance of FOXA1 plays an active role in conferring resistance to the therapy.

In the current study, the researchers took a genome-wide approach to dig deeper into how FOXA1 accomplishes the complex task of triggering metastatic behavior.

“Working with breast cancer cell lines in the laboratory, we discovered that FOXA1 reprograms endocrine therapy-

resistant breast cancer cells by turning on certain genes that were turned off before and turning off other genes. The new gene expression program mimics an early embryonic developmental program that endow cancer cells with new capabilities, such as being able to migrate to other tissues and invade them aggressively, hallmarks of metastatic behavior,” said first and co-corresponding author Dr. Xiaoyong Fu, assistant professor of molecular and cellular biology and part of the Lester and Sue Smith Breast Center at Baylor.

The researchers also discovered that FOXA1 does not act alone. Along with other factors, it activates a large number of enhancers that work together to synchronize genomewide cell reprogramming. HIF-2a is the top enhancer working with FOXA1 mediating the activation of prometastatic gene sets and pathways associated with poor clinical outcome.

Importantly, the researchers showed in laboratory cell experiments that an inhibitor of HIF-2a reduced migration and invasion of endocrine-resistant breast cancer cells expressing high FOXA1 activity.

“In collaboration with our colleagues from Harvard Medical School, we explored the possibility of transferring these findings to the clinic. We analyzed clinical metastatic breast cancer datasets and found reprogramming events that were similar to those found in our endocrine-resistant breast cancer cell models,” said Schiff, who also is a member of the Dan L Duncan Comprehensive Cancer Center at Baylor.

Taken together, these findings reveal details of the intricate mechanism FOXA1 triggers to induce metastatic behavior in endocrine-resistant breast cancer, which other reports have suggested also is present in other types of cancer, such as prostate and pancreatic cancer. In addition, the findings support further exploration of the possibility that inhibiting HIF-2a or other enhancer that control the expression of many genes in endocrine therapy-resistant breast cancer could be translated into effective therapeutic strategies.

“Working with breast cancer cell lines in the laboratory, we discovered that FOXA1 reprograms endocrine therapy-resistant breast cancer cells by turning on certain genes that were turned off before and turning off other genes. The new gene expression program mimics an early embryonic developmental program that endow cancer cells with new capabilities, such as being able to migrate to other tissues and invade them aggressively, hallmarks of metastatic behavior.”

DR. XIAOYONG FU, ASSISTANT PROFESSOR OF MOLECULAR AND CELLULAR BIOLOGY AND PART OF THE LESTER AND SUE SMITH BREAST CENTER AT BAYLOR

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| BIOSCIENCE TODAY |

| genome reprogramming |

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| genome mapping |

| BIOSCIENCE TODAY |

Unprecedented exploration generates most comprehensive map of cancer genomes to date

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| BIOSCIENCE TODAY |

| genome mapping |

A

n international team has completed the most comprehensive study of whole cancer genomes to date, significantly improving our fundamental understanding of cancer and signposting new directions for its diagnosis and treatment.

Published in Nature, more than 700 researchers have analysed more than 2600 samples from 38 cancer types ranging from common cancers like colorectal and breast cancers, to rare cancer types including pancreatic and brain cancers.

This analysis has enabled researchers to create the first complete atlas of genomes to compare the cancers and find the common mutations between them.

The atlas has been created by an effort known as PCAWG – the Pan Cancer Analysis of Whole Genomes or the Pan-Cancer Project – which has been a collaborative effort of groups from the International Cancer Genome Consortium who agreed to put thousands of sets of patient genome data together and reanalyse these samples using cloud computing.

University of Melbourne Professor Sean Grimmond, who holds the Bertalli Chair in Cancer Medicine, led the Australian efforts which contributed approximately 10 per cent of primary samples from a broad range of tumours including pancreatic, melanoma, neuroendocrine, and ovarian cancer.

Researchers found on average any given tumour has four to five key mutations – changes to the genetic blueprint – that are responsible for driving that disease.

Those mutations can vary a great deal for each cancer type.

“It demonstrates better than ever before how similar damage can cause cancer in different tissues – implications mean that for example a breast cancer drug could be effectively used to treat an oesophageal cancer.”

The atlas also provides insight for challenging cancers where the tissue of origin is not known by identifying patterns of damage across various cancer types.

“If we don’t understand where a cancer comes from, we can’t even rely on traditional clinical approaches to treatment,” Professor Grimmond said.

Having a harmonised dataset enables international researchers to learn from one cancer treatment and applies those findings to another using a cloud computing portal.

Researchers say further research with much larger datasets are required to enable precision medicine to truly become a reality.

Dr Peter Campbell, member of the Pan-Cancer Project steering committee and Head of Cancer, Ageing and Somatic Mutation at the Wellcome Sanger Institute in the UK said: “This work is helping to answer a long-standing medical difficulty, why two patients with what appear to be the same cancer can have very different outcomes to the same drug treatment. We show that the reasons for these different behaviours are written in the DNA. The genome of each patient’s cancer is unique, but there are a finite set of recurring patterns, so with large enough studies we can identify all these patterns to optimize diagnosis and treatment.”

Professor Grimmond said this atlas provides a solid foundation to understand which genes and which pathways may be damaged in each cancer type.

Dr Tom Hudson, Chief Scientific Officer at AbbVie and a founder of the International Cancer Genome Consortium said: “The completion of this project represents the culmination of more than a decade of ground-breaking work in studying the cancer genome.

When we launched ICGC in 2007, an initiative of this magnitude was unprecedented. I am thrilled that the scientific community has come together to produce this comprehensive study, which enhances our understanding of cancer and fosters the development of new medicines for cancer patients.”

“This research will help identify what types of genetic test are needed for each cancer type – filling in potential existing gaps that we did not even know were there,” Professor Grimmond said.

The Australian research groups involved include the University of Melbourne, Peter MacCallum Cancer Centre, QIMR Berghofer, Garvin Institute, University of Queensland, and Melanoma Institute of Australia.

Previously researchers were aware of one or two drivers.

Researchers say understanding that number and realising the complexity in each patient is an important step in working out where else to look when diagnosing cancer patients.

“This work is helping to answer a long-standing medical difficulty, why two patients with what appear to be the same cancer can have very different outcomes to the same drug treatment. We show that the reasons for these different behaviours are written in the DNA. The genome of each patient’s cancer is unique, but there are a finite set of recurring patterns, so with large enough studies we can identify all these patterns to optimize diagnosis and treatment.”

DR PETER CAMPBELL, MEMBER OF THE PAN-CANCER PROJECT STEERING COMMITTEE

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| training and education |

| BIOSCIENCE TODAY |

The hidden way to fill vacancies, train and retain The BSc (Hons) Biomedical Science (pathology lab based) degree apprenticeship has been developed through consultation with pathology laboratory employers and is co-delivered, meeting the requirements for a Healthcare Science Practitioner (Biomedical Scientist) apprenticeship.

The programme has expanded rapidly over the past couple of years as the university has worked closely with employer partners to offer this industry-relevant programme and meet employer workforce development needs.

I am passionate about Salford and about increasing the opportunities for individuals across the region and apprenticeships are the perfect route for people to pursue a career across a number of different sectors.”

TRAIN AND RETAIN

Shane Rhodes, Apprentice Biomedical Scientist, Manchester Royal Infirmary

This alternative route to higher level qualifications can be accessed by your current employees or used as a tool to attract new talent to your business.

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Deborah Seddon, Haematology and Blood Bank Manager, Salford Royal NHS Foundation Trust “We are currently supporting an employee through the BSc (Hons) Biomedical Science apprenticeship programme at the University of Salford. The initial interest within the NHS in apprenticeships came from the impact the levy was having on our budget.

I really believe apprenticeships are the way forward for our career – being able to grow your own talent and nurture the individual along the way results in a more knowledgeable Biomedical Scientist at the end.

The apprentice will have the opportunity to encounter more situations with support before they start working alone. I also believe it is healthy to have employees on such training programmes in the department as it keeps everyone on their toes – we are all continually refreshing our knowledge of developments in the field.

“The Biomedical Science degree apprenticeship and my role within the haematology and transfusion lab at Manchester Royal Infirmary go hand in hand - the on the job learning in the workplace really helps to consolidate the knowledge and theory from the classroom. If you are looking to get into a career as a Biomedical Scientist, then it really is a no brainer to go down the apprenticeship route – the real-world experience in the lab makes you such an asset to the team right from day one.”

APPRENTICESHIP FUNDING The apprenticeship levy was introduced in April 2017 and requires all employers operating in the UK, with a pay bill of over £3 million each year to invest in apprenticeships.

The funding policy supports the changes to the way apprenticeships in England are paid for, underpinned by the apprenticeship levy of 0.5% of the annual pay bill for companies paying over £3 million per year.

There is also a co-investment model for companies who will not be paying into the levy. The government will cover 95% of the cost of the apprenticeship and the employer will only have to contribute the remaining 5%. Once payments have been declared to HMRC, employers will now have access to a digital apprenticeship account from which they will be able to access funding to pay for apprenticeship training.

There is also an opportunity for larger levy paying organisations to transfer up to 25% of their unspent levy funds to other, smaller employers to support their workforce development.

GET IN TOUCH NOW TO FIND OUT MORE: apprenticeships@salford.ac.uk 0161 295 4612

46

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Our Healthcare Science Practitioner Degree Apprenticeship allows students to exit with a full BSc (Hons) Biomedical Science degree qualification. / Apprenticeship funding available / Delivered on a part-time, day-release basis / Increase retention by offering your workforce the chance to develop and progress / Tailor apprentices’ learning to your requirements Get in touch today to find out more: www.salford.ac.uk/apprenticeships apprenticeships@salford.ac.uk

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| drug delivery |

| BIOSCIENCE TODAY |

Medici Drug Delivery Systemâ„¢ - Osmotic Mini-Pump

48

| BIOSCIENCE TODAY |

| drug delivery |

Next Chapter of Intarcia’s Mini Pump for Diabetes Begins More than 2 years after the FDA derailed the trajectory of its novel treatment system for type 2 diabetes (T2D), Intarcia Therapeutics announced that regulators have accepted a resubmitted new drug application for the mini pump that delivers a continuous dose of exenatide.

More than 2 years after the FDA derailed the trajectory of its novel treatment system for type 2 diabetes (T2D), Intarcia Therapeutics today announced that regulators have accepted a resubmitted new drug application for the mini pump that delivers a continuous dose of exenatide.

sitagliptin. At the 2015 American Diabetes Association Scientific Sessions in Boston, onlookers crowded around Intarcia’s booth and had to be stopped from taking photographs during demonstrations of how the piston-fired minipump was quickly inserted under the skin.

According to the company’s statement, if approved, the matchstick-size ITCA 650 “would represent a new, twice-yearly delivery system of glucagon-like peptide-1 (GLP-1) receptor agonist for maintenance therapy of type 2 diabetes.”

Leading diabetes experts, including Julio Rosenstock, MD, of the Dallas Diabetes Research Center, and Robert R. Henry, MD, of the University of California at San Diego, attested to study findings that showed the potential value for payers of a tamper-proof device that could be inserted under the skin and left in place for up to 6 months. The device met safety end points of a cardiovascular outcomes study.

The osmotic mini pump technology, known as Intarcia’s Medici Drug Delivery System, involves no electronics and is also being studied for treatments of obesity and HIV, among other conditions.

The Prescription Drug User Fee Act date for FDA action on ITCA 650 is March 9, 2020, according to the company.

Today’s development marks a comeback for a T2D treatment system that many saw as a gamechanger in the summer of 2017, before setbacks let to several personnel changes. In 2018, Intarcia named Thane Wettig, formerly of Eli Lilly, to the new role of chief marketing officer and metabolic franchise head, and named Fred Fiedorek, MD, chief medical officer and global head of Regulatory Affairs.

Intarcia’s therapeutic solution tackles one of the most vexing problems in diabetes care: medication adherence. In clinical trials, the ITCA 650 produced more than twice the reduction in blood sugar and 3 times the weight loss as a popular oral medication,

49

During a session at ADA 2015 in Boston, Rosenstock described the phase 3 ITCA 650 results as “transformational.” At 39 weeks, among patients with glycated hemoglobin (A1C) between 7.5% and 10%, the average reductions for patients taking the lower dose of 40 mcg was 1.1%; for patients not taking background sulfonylureas, the average reduction was even lower at 1.7%.

But the momentum halted on September 27, 2017, when word came that FDA had sent the company a complete response letter (CRL). A notice from Intarcia stated that “the company received clear and constructive guidance from the agency regarding manufacturing aspects of the CRL and is on a clear path to move forward.”

| news |

| BIOSCIENCE TODAY |

watching the Chimpanzee Conga: How humans learnt to dance The evolution of human dance has been studied by psychologists in chimpanzees Researchers from the University of Warwick, Durham University and Free University of Brussels found two chimpanzees performed a duo dance-like behaviour, similar to a conga-line Behaviours displayed by the chimpanzees forces an interest in the evolution of dance as humans are no longer the only ape species where it takes two individuals to tango.

Psychologist observing two chimpanzees in a zoo have discovered that they performed a behaviour hitherto never seen, they coordinated together in a rhythmic social ritual.

Two chimpanzees house in a zoo in the US have sparked the question about how human dance evolved after being observed performing a duo dance-like behaviour, similar to a human conga-line.

In the paper ‘Coupled whole-body rhythmic entrainment between two chimpanzees’ published in the Journal Scientific Reports, researchers led by the University of Warwick found the levels of motoric co-ordination, synchrony and rhythm between the two female chimpanzees matched the levels show by orchestra players performing the same musical piece.

Other species have been shown to be able to entertain by moving to the pace of a rhythmic tempo by an external stimulus and solo individuals, however this is the first time it hasn’t been triggered by nonhuman partners or signals.

Although the newly described behaviour probably represents a new form a stereotypy in captivity in this great ape species, the behaviour forces scientists interested in the evolution of human dance to consider new conditions that may have catalysed the emergence of one of human’s most exuberant and richest forms of expression.

Dr Adriano Lameira, from the Department of Psychology at the University of Warwick comments: “Dance is an icon of human expression. Despite astounding diversity around the world’s cultures and dazzling abundance of reminiscent animal systems, the evolution of dance in the human clade remains obscure.

“Dance requires individuals to interactively synchronize their whole-body tempo to their partner’s, with near-perfect precision, this explains why no dance forms were present amongst nonhuman primates. Critically, this is evidence for conjoined full-body rhythmic entrainment in great apes that could help reconstruct possible proto-stages of human dance is still lacking.”

The researchers report an endogenously-effected case of ritualized dance-like behaviour between two captive chimpanzees – synchronized bipedalism. By studying videos they revealed that synchronisation between individuals was non-random, predictable, phase concordant, maintained with instantaneous centi-second precision and jointly regulated, with individuals also taking turns as “pace-makers”.

50

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Rb

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85.4678

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Sr

2 8 18 18 8 1

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2 8 18 8 2

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Y

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Ba

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137.327

88

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U

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55.845

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61

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Np (237)

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63

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Eu

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Sb

83

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207.2

114

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2 8 18 18 5

52

Te

208.9804

115

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162.5

Terbium

97

66

98

68

164.93032

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167.259

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99

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Californium

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2 8 18 30 8 2

69

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Tm

100

Einsteinium

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Fermium

70

168.93421

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Lv (293)

2 8 18 32 30 8 2

101

Md (258)

Yb

2 8 18 32 8 2

71

2 8 18 32 32 8 2

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2 8 18 32 31 8 2

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2 8 18 32 18 6

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Lr (262)

conjugated nanostructures tungsten carbide

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2 8 18 32 32 18 6

117

(294)

2 8 18 32 32 8 3

86

2 8 18 32 32 18 7

118

Xe

2 8 18 18 8

131.293

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2 8 18 32 18 8

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2 8 18 32 32 18 8

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126.90447

Livermorium

173.054

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53

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Br

2 8

20.1797

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silver nanoparticles 65

35

127.6

84

2 8 7

Ne

35.453

Tellurium 2 8 18 32 18 5

Cl

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Helium

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Chlorine

78.96

Bismuth 2 8 18 32 32 18 4

17

Selenium

121.76

2 8 18 32 18 4

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32.065

34

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He

Fluorine

S

Antimony

Lead 2 8 18 32 32 18 3

2 8 18 5

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Sulfur

74.9216

Tin

82

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Arsenic

118.71

2 8 18 32 18 3

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As

F

15.9994

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72.64

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114.818

200.59

112

Si

Indium

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69.723

2 8 18 18 2

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O

14.0067

28.0855

2 8 18 3

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Nitrogen

Silicon

Gallium

112.411

Gold

2 8 18 32 32 17 1

31

Cadmium

196.966569

158.92535

2 8 18 32 25 9 2

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2 8 3

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N

12.0107

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2 8 18 2

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Silver

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2 8 18 18 1

Al

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C

10.811

65.38

107.8682

195.084

157.25

Europium

47

Platinum

Meitnerium

151.964

Samarium

78

192.217

2 8 18 32 32 14 2

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106.42

Iridium

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2 8 18 24 8 2

Pd

Zn

Copper

Palladium

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46

102.9055

2 8 18 32 14 2

63.546

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Rhodium

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58.6934

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Ruthenium

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58.933195

Iron

Technetium

183.84

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2 8 18 13 1

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144.242

238.02891

Fe

54.938045

95.96

Neodymium 92

26

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60

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2 8 13 2

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42

180.9488

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178.48

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51.9961

92.90638

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Niobium

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58

Nb

24

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91.224

138.90547

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47.867

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2 8 18 18 8 2

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88.90585

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22

44.955912

87.62

Cesium

Fr

Sc

2 8 9 2

Scandium

Strontium

132.9054

87

21

6

2 3

Boron

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6.941

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