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Exon skipping: making sense out of nonsense

RNA
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Associate Professor Michela Alessandra Denti, Principal Investigator of the Laboratory of RNA Biology and Biotechnology at the Centre for Integrative Biology of the University of Trento, discusses how modulation of RNA splicing can represent a cure for inherited diseases

RNA impacts nearly every aspect of gene expression and it is now clear that a large portion of human genetic diseases is caused by mistakes in RNA metabolism. It has become progressively evident that RNA is not just a carrier of genetic information, but also a catalyst and a guide for sequence-specific recognition and processing of other RNA molecules.

The growing body of knowledge concerning RNAs is opening up exciting and unprecedented avenues for research: RNA molecules are today, at the same time, targets of therapeutic intervention and novel therapeutic molecules to treat human diseases.

RNA splicing

‘RNA splicing’ is a process that all messenger RNAs (mRNAs) undergo in the cell. Once transcription of a gene begins in the nucleus, the transcript undergoes a complex series of processes all devoted to the production of a mature mRNA, collectively dubbed ‘‘mRNA processing’’. One of these events, called RNA splicing, consists in the removal of intervening sequences (‘‘introns’’) and the joining of the coding portions of the transcript (‘‘exons’’).

RNA splicing is a major way by which the cell can induce transcriptional diversity, mainly through alternative splicing, and apply a fine control on this diversity. The proper recognition of introns and exons is mediated by cis-acting sequences on the pre-mRNA and trans-acting protein factors, constituting the splicing machinery.

Gene mutations can alter RNA splicing

Several gene mutations, which cause different rare inherited diseases, affect the splicing of specific mRNAs. Generally, mutations residing in introns are categorised as splicing mutations because the amino acid sequence of the protein is not altered, thus the problem most likely concerns proper splicing. However, splicing mutations can also be found in the exons, altering or not the coding sequence. In this case, their identification as a splicing mutation is much more difficult, as it requires analysis of the splicing pattern. Today it is believed that more than 50% of mutations act by altering the splicing pattern. Their effect can be retention of a part of an intron or the use of alternative splice sites, ultimately causing the insertion of a stop (“nonsense”) codon. This, in turn, would cause the messenger RNA to produce a truncated, hence not functional, protein. Correct identification of these mutations is of pivotal importance for the development of therapeutic approaches.

Modulating RNA splicing as a cure for inherited diseases

At variance with mainstream gene therapy approaches, which aim at replacing the mutated gene with a functional DNA copy of the gene itself, the therapeutic approach called “exon-skipping” aims at correcting the mRNA transcribed from the mutated gene. By introducing small RNA molecules, scientists mask the mRNA to the attack of the splicing machinery, inducing it to jump certain portions of the mRNA, thus restoring the correct message. Exon-skipping holds a great deal of promise as a potential cure for genetic diseases, and several clinical trials in Duchenne Muscular Dystrophy have supported the notion that the technique could one day become commonplace for many other inherited diseases.

Aside from splicing mutations, antisense-mediated splicing-correction approaches can potentially be utilised for the correction of missense and nonsense mutations, as well as for small insertions and deletions. In all cases where a mutation causes the introduction of a stop codon or frameshift leading to premature termination of the transcript, the possibility to interfere with the proper recognition, by the splicing machinery, of the exon carrying the mutation (therapeutic exon skipping) can be the right strategy to follow. The result of this approach is a shorter mature mRNA, missing the portion encoded by the skipped exon, but resulting in a restored protein. Such an approach has been proven successful to restore dystrophin in the muscles of Duchenne Muscular Dystrophy patients.

The most widely studied approach for the correction of aberrant splicing is the use of antisense oligonucleotides, short synthetic molecules that target the pre-mRNA and that can be delivered to the affected tissue by local injection or through intravenous injection and delivery via the circulation. As the effect of antisense oligonucleotides is time-limited, to have a durable effect repeated administration is required. In this view, scientists are also studying the possibility of using engineered small antisense RNA molecules, produced by endogenous transcription of DNA vectors provided to the affected organ using viral or non-viral delivery systems.

RNA splicing is an extremely complex and fundamental cellular process that has been so fare barely considered as a therapeutic target, even if it can be seen as a highly appealing one for its importance in the cell context. The ability to modulate splicing can in fact offer several advantages over other conventional gene replacement approaches.

By definition, antisense-based therapeutic approaches act following base-pairing with their mRNA target, thus giving the possibility of obtaining a great specificity of action. Since they act at the mRNA level, the endogenous transcriptional regulation of the target gene is always maintained. This means that the therapeutic effect is obtained only where and when the target pre-mRNA is present. Splicing-correction approaches also allow a fine-tuning over the relative abundance of splicing isoforms because, by acting at a pre-mRNA level, it is relatively easy to modulate their ratio. The availability of several different molecular tools that can be used to manipulate splicing renders these approaches a versatile and promising strategy for the multitude of genetic diseases known today.

To overcome the challenges of the exon-skipping strategy, at the end on 2012 several key stakeholders (scientists, clinicians, regulators, industry and patients) came together in COST (European Cooperation in the field of Scientific and Technical Research) Action BM1207 ( www.exonskipping.eu ). This COST Action aims to advance the development of antisense mediated exon skipping for rare diseases, using Duchenne muscular dystrophy, for which this approach is currently tested in phase 3 clinical trials, like a showcase. Through networking, participants belonging to 18 different countries, intend to allow the clinical implementation of antisense-mediated exon skipping for as many rare disease patients as possible.

 

Prof. Michela Alessandra Denti

Principal Investigator

Laboratory of RNA Biology and Biotechnology,

Centre for Integrative Biology, University of Trento, Italy

michela.denti@unitn.it

http://www.unitn.it/en/cibio/11886/laboratory-rna-biology-and-biotechnology

Addressing the world’s water shortage

water
Close up child hands with water drops from old grunge brass faucet on green bokeh background. Water shortage and earth day concept.

Acute shortage of drinking water reserves across the globe is one of the biggest problems these days. According to the study conducted by NASA in cooperation with the University of California on the underground natural reservoirs of water for the period of 2003-2013, the water supplies in underground aquifers are rapidly shrinking. Just over 30 percent (13 out of 37) of the largest underground water reservoirs are drying up at the moment. The fact that 35 percent of the world’s drinking water comes from these underground sources means the situation could be described as critical.

According to the Agency for Regulation of Natural Monopolies, the groundwater reserves of Kazakhstan are estimated at 19 billion cubic meters, with an annual intake of water around 1.4 billion cubic meters. Providing the population of all regions with high-quality drinking water is one of the most urgent and difficult problems for the ecological security of Kazakhstan. According to the Ministry of Health of the Republic of Kazakhstan, the current state of sewerage systems resulted in a lack of sanitary and epidemiological welfare of the country’s population. Thus, the quality of water from the 1 category open reservoirs used for centralised water supply in Kazakhstan declined on chemical indicators compared to 2009. Out of 1,989 water samples, 151 (7.6%) did not meet the standards of microbiological indicators – 4.5%.

The problem with drinking water purification is that it requires the joint efforts of industry, scientists and government together. There are a number of government programs aimed at addressing the problem.

Thus, in the years 2002-2010 the “Drinking Water” industry program was launched by the government to provide settlements with reserves of drinking water. In 2011, the Ministry of Economic Development and Trade has planned an industry program called “Ak Bulak” to ensure settlements with drinking water for the years 2011-2020. The state programs developers indicate that one of the most affordable and effective ways to improve the quality of water is the use of individual purifications, mobile and stationary water purification filters. Thus, the Interdisciplinary Research Complex was established in 2006 at the University, and since 2010 has been working with the Intergovernmental Organization “Joint Institute for Nuclear Research” (JINR) on the development of filters based on track membranes.

Analysis of the literature and patent documentation in the field of water treatment with the use of track membranes has indicated significant potential and limitless possibilities of this technology. At the heart of track membrane a polyethylene terephthalate film is irradiated with a heavy ion accelerator DC-60. After irradiation, the film is subjected to chemical etching, in which the latent tracks are converted into pores of the necessary diameter.

Filters based on track membranes are considered as a logical solution to the problems arising in the processing of drinking, technical and ultrapure water. This is due to a number of advantages of membrane technology as compared to conventional water treatment systems, such as the stability of the purification quality – even with substantial fluctuations in the composition of the source water, the compactness of the equipment, high level of automation, and low operating costs. Membrane technology produces drinking water not only safe in chemical and microbiological terms, but also physiologically full in terms of macro- and microelement composition. As a result of this project, “Bulak-M”, a line for the production of individual filters was launched and entered the retail market and was later exported to African countries.

It is notable that at this point in Kazakhstan no enterprise except L.N. Gumilyov Eurasian National University is carrying out a complete production cycle of track membranes. Thus, in the high technology sector, there is no alternative import substitution, and demands of the consumer market are replenished by the products of foreign companies.

Engineering profile laboratory for the development of membrane technology- based accelerator DC-60 has become a starting point for the development of innovative technologies focused on the result of high demand. The accelerator DC-60 is the first major research nuclear physics facility complex established in the CIS. In the process of its design the most advanced physics ideas and technical solutions were used to create one of the world’s best-in-class accelerators.

The research group consists of scientists, graduate and undergraduate students, and PhD students of the L.N.Gumilyov Eurasian National University.

Today, it is evident that the research activity of the complex is proof of the successful integration of education and science in solving the urgent problems of mankind. Due to the persistently increasing of the world’s population, this problem of drinking water has reached a global scale. Therefore, it is hard to deny that an interdisciplinary approach in this area is one of the most effective. Basically, this is exactly what the creation of the research complex was supposed to bring in the ecology studies and life science.

 

Jamilya Nurmanbetova

L.N.Gumilyov Eurasian

National University

Tel: +77172 709500 (31-309)

enu@enu.kz

www.enu.kz

A number one funding source for Russian basic science

Alexander Khlunov, Director of the Russian Science Foundation (RSF) gives an overview of how the Foundation supports research throughout the country

The Russian Science Foundation (RSF) was launched in November 2013; its operation is governed by a special federal law. Incorporated as a foundation, RSF proves a more flexible and effective funding tool in comparison with other institutions that finance science in Russia.

RSF’s mission is to identify the most promising scientific projects and highly efficient and result driven scientists, as well as to actively engage the country’s young researchers in science.

Its support of research relies on the principle of competition and RSF organises a variety of funding competitions to appeal to the following research areas:

  • Basic and applied research projects initiated by scientific departments, organisations and universities. Here, the Foundation reviews projects carried out by small teams set up for that purpose.
  • Support to research institutions and universities. In this area of operation, RSF seeks out programmes led by research institutions and geared towards ground-breaking research. Each programme must include a number of large-scale projects with a significant scientific, economic and social impact.
  • Establishment of up-to-date laboratories and departments in research institutions and universities. To make this happen, the Foundation reviews projects submitted by long-established or newly-created labs.
  • Promotion of international scientific and technological collaboration. RSF invites projects carried out by international teams working together to solve a particular problem.

RSF provides funding opportunities to projects across 9 branches of knowledge: mathematics, computer and systems sciences; physics and space science; chemistry and materials science; biology and life sciences; basic medical research; agricultural sciences; Earth sciences; humanities and social sciences; engineering sciences. In 2014, over a third of all projects supported by RSF involved basic and applied research in the socially relevant field of life sciences.

RSF is Russia’s largest foundation engaged in funding of basic and applied research. Its annual budget dynamics is shown in the chart below.

The Foundation is supervised by the supervisory board, chaired by the Assistant to the President of the Russian Federation Andrei Fursenko. The Board has 15 members, counting among themselves high-ranking scientists, members of the Academy of Science and officials, including the Minister of Science and Education and the Parliament Members.

Over 3000 Russian and 1000 foreign scientists sit on the Foundation’s various review boards.

The project evaluation process is shown in figure 2 and spans several review stages, including individual evaluations and discussions at sectional review boards. RSF keenly assesses the professional expertise of the project leaders. In order to submit a funding proposal, the team leader should provide a list of publications by the team members over a 5-year period preceding the application, and be able to confirm his or her relevant experience in research project execution and educational activities.

Following just 1 year of operation the Foundation’s achievements are already impressive:

  • RSF processed 110,000 funding applications from researchers in Russia and abroad.
  • 1120 projects and programmes, 383 research institutions and universities from 51 regions in Russia were awarded funds by RSF
  • 161 established labs engaged in the world-class research were supported by RSF.
  • 38 new labs tackling the highly relevant problems with a societal and economic impact were established with RSF’s financial support.
  • 16 development programmes of research institutions and universities received funds from RSF in order to boost their research staff’s career potential and conduct research and development according to the internationally recognised standards
  • 16 000 scientists from Russia and abroad are engaged in the RSF-funded projects, most of whom are aged 39 or younger.

RSF is open to collaborations and works to extend its international cooperation. The Foundation engages over 200 foreign scientists, with more than 1000 experts from 46 counties participating in proposal reviews. In June, 2015 the Foundation oversaw the launch of the first joint competition together with DFG, the German Research Foundation.

 

Alexander Khlunov

Director

Russian Science Foundation

www.rscf.ru

The climate’s beating heart: Myths and maths

climate

It stores heat, greenhouse gases and gives back at a measured rate. It is the World’s Ocean. As a player in our understanding and predicting the climate on Earth, it has had a supporting role to the atmosphere. But things have changed and it is moving to center-stage.

To a great extent, our understanding of the climate comes from massive mathematical models. There are only a few around the world that make the cut in the Intergovernmental Panel on Climate Change’s list (see www.ipcc.ch ).

The idea of a full climate model, now often known as an Earth system model, is to create a mathematical replica of the Earth. We have only one Earth and so experimentation in the normal sense is impossible on the full climate system. But the computational output of a climate model can tell what is likely to happen under a particular scenario, for instance from a certain pattern of greenhouse gas emissions in the future.

The primary concern in climate change is the heating of the air that sustains life on Earth. We know the ocean is involved as heating leads to ice melting and that will lead to sea level rise. A myth is that the Ocean is a passive partner in this process. Its role in regulating the climate and moderating its change is enormous. But, in the twentieth century, climate models treated the ocean as a slab. If it is so important, how did they get away with such a crude representation? The answer lies in what the models were then used for: to test the prediction that our climate would be warming over the long term, upwards of fifty years. On such time scales, the variability of the ocean is not that important.

The climate community accepts that the case for climate change, as well as its causes in anthropogenic emissions, is now closed. The focus has shifted to prediction on shorter time-scales, driven by an interest in what will happen in five, ten, or twenty years. The thinking is that we are committed to considerable climate change already and we need to know how it will impact us in specific ways. On this time scale, the ocean will play a critical and active role.

It is a myth is that we know everything about the ocean from taking measurements. Of course, we know a lot more than we did in the past. This has been made possible through international efforts, such as the ARGO project ( www.argo.net ), and the availability of new autonomous vehicles taking measurements. These so-called gliders can be viewed as waterborne drones. But the ocean is vast and deep and what we observe is only a small fraction of the whole. So, how do we fill in all the missing information? The answer is again to use a mathematical model. We know how the ocean must work from its underlying physics. It all comes from classical mechanics and the mathematical equations were formulated over 200 years ago. Although new simplifications are coming along all the time, the basic set of equations used in the models have remained the same.

How does this help us fill in all the missing information? The picture to have here is of a massive three dimensional grid filling the ocean, both in breadth and depth. A full description of the ocean would consist of an assignment of physical variable values at each node of this grid. The physical variables will include: flow velocity, temperature, pressure, and density among others. The observations, coming from all these measuring instruments, will tell us the values of these quantities at some of the nodes. It is a myth that the remaining values can be found just by interpolation; there are simply too few nodes reporting and too many possibilities for how the interpolation might work. This is where the mathematical equations come in as they can tell us, through computation of the model, what constrains the physical variables across the entire grid. This process of merging data and model is known as data assimilation (DA).

It is hard to underestimate the importance of DA. While much work is devoted to big data, it is often not recognised that data comes from different sources and that fact influences how we can effectively tease out the most accurate information. DA works as follows: the model gives an estimate of the system state, which is in our case an assignment of physical variable values at each grid node, and is evolving in time in a way that is provided by solving the equations on a large computer. At observation times, two things should happen: first, the estimate of the system state needs to be adjusted in light of the observational data. Inevitably, the inaccuracies in the model will have driven the estimate off track and there would be little hope of a match with observations. Secondly, certain parameters set in the model will need adjustment in the light of observations coming from the real world. This is a way in which the model can learn from observations.

This all sounds simple enough: somebody just goes in and switches out a few values in the model. But to ensure physical consistency, we cannot perform this task arbitrarily and the whole process ends up being as complex as the underlying model itself. The issues are further exacerbated by the fact that the observations are often not of the physical variables of the model, but something related to them by a further model!

There are a plethora of mathematical challenges in data assimilation, particularly for the ocean. The hardest, and arguably most important, is simultaneously dealing with the inherent nonlinearity in the system and its high dimension. The high dimension comes from the fact that we have a number of physical variables at each grid node and the dimension is the product of the number of grid nodes, of which there will usually be a million or more, and the number of variables. We have good DA methods for nonlinear systems in low dimensions as well as methods that work in high dimensions, but these involve linear approximations that may be broken by an underlying nonlinear system. This issue of dealing with nonlinearity versus dimension is, in my mind, one of the greatest mathematical challenges of our day. We will not get the ocean correct until we perform data assimilation much better, and we cannot predict the climate on decadal time-scales until we get the ocean right.

 

Christopher Jones

Guthridge Distinguished Professor

RENCI and Department of Mathematics

University of North Carolina at Chapel Hill

Director

Mathematics and Climate Research Network

Department of Mathematics, University of North Carolina at Chapel Hill

Tel: +1 919 923 3569

ckrtj@amath.unc.edu

www.mathclimate.org

The power of basic research

Rebecca Keiser, Head of the National Science Foundation’s Office of International Science & Engineering sheds light on why basic research is integral to the progress of science

The touchscreen on your cell phone. The bar code scanner in a grocery store check-out line. Doppler radar for weather prediction and GPS – these are all part of everyday life. None would be possible without basic scientific research.

And, they would not be possible without the National Science Foundation (NSF), the only U.S. government agency charged with supporting fundamental research in all fields of science and engineering. For more than 70 years, NSF has invested in pioneers. Our mission is to promote the progress of science; advance the national health, prosperity, and welfare; and secure the national defense. Each year, we make about 11,000 awards, chosen after a rigorous review process from more than 50,000 proposals. NSF funding provides resources to individual scientists and engineers, students, teachers, institutions and centers, in all 50 states and U.S. territories.

We funded the early innovators of the Internet and supported robotics and synthetic biology when they were nascent fields. Through our science, technology, engineering and mathematics (STEM) education programs, we’ve also supported the next generation of scientists and engineers, students who have gone on to make astounding discoveries, win Nobel Prizes and even start a company called Google.

The beauty of basic research, the kind NSF funds, is that it can take us anywhere. Discoveries lead to new questions and new discoveries – and then usually more questions – and down the line society has an innovation like 3D printing (3 of the patented technologies used in this process were developed with NSF support). Even slightly odd research questions – like how are human populations distributed with respect to altitude? – can lead to insights used today by the food, semiconductor and biomedical industries.

Broadly speaking, investing in basic research expands knowledge. It teaches us more about the molecules that make up our bodies, the bodies that make up our universe, and everything in between. Yet basic research is also a major economic driver.

The spectrum auction policy used by the U.S. Federal Communications Commission, for example, came out of NSF-funded economic research. This method for apportioning airwaves has brought in millions of dollars in government revenue. Early NSF investment in digital wireless technology laid the groundwork for the creation of Qualcomm, now a global company worth more than $100bn.

Today’s discoveries are often made in a global setting. More than ever before, research involves collaborators from around the world. Over the past 20 years, the percent of all scientific papers that are internationally co-authored has more than doubled, according to a July Plos One article. In fact, the more elite a scientist is, the more likely it is that they collaborate internationally.

NSF places a high value on the importance of international cooperation; it, too, has tangible benefits to both the U.S. and our international partners.

Our work with Japan and Chile, for example, has helped scientists comprehend earthquake causes and effects, ultimately helping countries better understand and plan for these hazards. A partnership between NSF and the UK’s Biotechnology and Biological Science Research Council collected a diverse group of researchers to tackle the issue of nitrogen fertiliser pollution. The ensuing research projects, still ongoing, could help develop crops of the future.

Working together ensures we leverage both scientific resources and scientific funding. With our international awards, NSF funds the U.S. researchers, while our partner agencies abroad fund their portion. This enables engineers from the University of Nevada-Las Vegas, for example, to collaborate with leading roboticists in Korea on artificial muscle technology.

It gives a graduate student studying marine microbes the chance to spend a summer working in a Japanese lab specialising in that research. Our world is facing major challenges – a changing climate, growing pressures on resources like energy and water, emerging infectious diseases. Science and engineering will play a major role in tackling these challenges. Continued support of basic research – and continued collaborations between NSF and countries around the world – will ensure the health and prosperity of citizens around the world.

 

Rebecca Keiser

Head of the Office of International

Science & Engineering

U.S. National Science Foundation

info@nsf.gov

www.nsf.gov

The challenge of recruiting more women

Recently-installed IET President Naomi Climer has made it her mission to improve recruitment of women into engineering and technology roles, with oil and gas just one area under the spotlight

Name a famous engineer or technologist and most people would undoubtedly mention Steve Jobs, Bill Gates, Isambard Kingdom Brunel or George Stephenson. Being optimistic, perhaps Ada Lovelace or Martha Lane Fox might spring to mind.

But most people would, I think, struggle to name many women who have influenced the history of engineering or technology – which makes it unsurprising that young girls are not drawn to an engineering and technology career.

Why does this matter? It matters because the world needs more engineers and technologists if our economies are to continue to grow, and also because diverse teams are more innovative. The truth is that a more representative workforce would be a good outcome for everyone – not just for women. A lack of diversity means we are missing out on ideas and innovation that come from different perspectives.

To achieve a more diverse workforce, we need more role models at every level to inspire young women by showing them what engineering and technology could look like for them. The world has changed a lot for women over the past 100 years. We earned the right to vote and have broken down boundaries in many professions – for example, 50 per cent of GPs are now women, so why are we not seeing more modern-day female champions emerging in engineering and technology?

Less than one in 10 engineers in the UK today are women. This is a result of a number of factors – from the careers, advice girls are given in schools, to schools not instilling girls with the confidence to opt for science and maths at A-level. But, it is also due to some employers needing to make their approach to recruitment and retention more female-friendly.

More female-friendly retention and recruitment practices are a vital part of solving the challenge. There are skilled women qualified to take up existing roles, but many are leaving the profession as soon as they graduate and I believe there are things that companies can do to attract and retain these qualified women. The whole of the engineering profession – including men – needs to pull together to help win this battle. There is no quick or simple fix. Instead, we need many small and subtle changes over time.

Promoting female role models

Our recent Skills Survey found that 57 per cent of engineering businesses don’t have gender diversity initiatives in place. This could be as simple as things like routinely reviewing recruitment language or marketing images for engineering jobs. There are great examples of companies who have consistently worked on their diversity and it does make a difference.

I would like to see companies over a certain size measure and publish their diversity figures including recruitment, retention, promotion and pay. This would help them to focus on the issue and also benchmark themselves against what other companies are achieving.

I would like to think that in 10 years’ time, many more people would be able to name a minimum of five women in engineering and technology. But this can only be achieved if we do more to create and promote these female role models and ambassadors. We need consistent efforts from parents, schools, and universities to encourage more girls to study Science, Technology, Engineering and Mathematics (STEM) subjects and aspire to a career in engineering. From industry, we need a concerted effort to attract and retain female engineers and technologists who can help address the UK’s shortage of engineers – and bring a new perspective and skill set to the world’s big engineering and technology challenges.

 

Naomi Climer

President

The Institution of Engineering and Technology

www.theiet.org

 

The Impact of engineering in biology and medicine: the biomedical engineer (BME)

In 2014, WHO stated: “trained and qualified biomedical engineering professionals are required to design, evaluate, regulate, maintain and manage medical devices, and train on their safe use in health systems around the world”1.

In response, the European Economic and Social Committee stated: “Biomedical Engineering is not simply a subset of modern medicine. Modern medicine predominantly secures important advances through the use of the products of biomedical engineering”2.

With this document as a start, two Euro-Parliamentarian Members, Dr Lara Comi and Dr Nicola Caputo, tabled two parliamentary questions asking why, different to the USA, the Horizon 2020 vision does not have a dedicated space for BME and why BME is not listed among the professions that the European Commission officially recognises. The European Commission answered that biomedical engineering is crucial in addressing many of the challenges found in the programme. So, what is happening? Why all this interest around the field of BME over the last few months? The answer is not easy to arrive at, but we can attempt it. BME represents one of those cases in which Academic research is perfectly aligned to manufacturing visions and missions, and both are supporting healthcare innovations that are directly impacting the wellbeing of European Citizens and increasing National healthcare systems and services cost-effectiveness. This chain is working so well that WHO is also benefiting from this. For instance, the initiatives that have seen the International Federation of Medical and BME, IFMBE, which is the world’s most important scientific society for BME and also an ONG officially recognised by the UN, supporting WHO on specific projects aiming to build capacities in low-income countries or to promote innovation making more affordable medical devices, are countless.

However, let us take a step back in order to understand better the context. BME is a key sector for European competitiveness. It presents a €100 billion-market size. In Europe, 20,000 companies work in this sector. This equates to 575,000 jobs and in terms of innovation, this is the first sector in patent applications – 10,412 – in 2012. Those numbers are growing very fast and the BME sector is becoming of strategic interest to Europe and other developed countries. For instance, the CNN reported in 2014 that BME was the first job in the USA for impact, growth and future prospects3. On the other hand, 90% of companies producing medical devices are SMEs and the product lifecycle is very short (18 months circa) making the time from research to the assessment to the adoption very short in comparison to other healthcare technologies (i.e. drugs). This is creating new challenges for the European Union that require a strong synergy between all the stakeholders and a proactive reaction from each actor.

What are the challenges for BME? The fact that the lifecycle of its main products, medical devices, is so short is one of the most significant challenges. Apart from inventing the future, BMEs are also called to invent how to sell it, proposing new business models that make sustainable the cycle of innovation and marketing, especially in the field of ICT for healthcare. Another huge challenge, very specific to BME, is that we do design technologies that are required, assessed, acquired and utilised by people other than engineers. If you design aircraft, you will most probably follow the specifications given by an engineer and your innovations will be assessed, acquired and even piloted by someone with the same background as yours. This means that they have been educated using the same language as the one you have been educated to, and most probably they will use this language to give you their specifications. If you work in medicine or biology, you will face that even the specification and the commissioning of new system requisites may require outstanding empathy, apart from a solid scientific basis and experience. Additionally, if you are a BME, you will mainly work in multi-disciplinary teams. You may work one day with a cardiologist and the day after with a neurologist, and you will need to understand as much as them about a cardiac cycle, Krebs cycle and mirror neurons, in order to understand deeply where your innovation can maximise your impact.

However, it does not matter how many years you have spent alternating books of physiology with those of electronics and computer science, at this moment the only opportunity you have, if you are trying to apply for a grant, is to select “other engineering” when you have to describe your field. From the Academic perspective, a BME’s community is continuously monitoring the evolutions of the relevant markets. For instance, two European Projects in the past years contributed to the harmonization of BME curricula in Europe: Biomedea and INTERREG CRH-BME.

In answer to these challenges, and considering the results of those projects, the Warwick Engineering in Biomedicine (WEB) group at the School of Engineering, the University of Warwick, have launched a new MSc programme in Biomedical Engineering. This one year programme takes into account the interdisciplinarity of the field and provides students with targeted modules addressing the needs of industry, healthcare providers and Academia. It covers classic topics of BME (i.e. biomedical signal processing, imaging, biological system dynamic modelling, biomechanics, tissue engineering, clinical engineering and health technologies design, system medicine) but also topics that are not traditionally delivered as part of BME degrees such as health technology assessment, procurement and management. This is important as BMEs graduating at Warwick have a concrete feeling of the complexity of the BME field and are never naïve to the challenges that an innovation has to face to move from the lab to the market. The design of this innovative Masters degree has been possible as WEB brings together the research expertise of more than 20 biomedical engineering academics and researchers working in very different areas of BME and coming from very different professional experiences, not to mention Nations and continents. In fact, walking in the corridors of the School of Engineering, and particularly in the new building dedicated to WEB, students can engage with key figures within the main scientific international organisations on BME in UK, Europe and Worldwide, which practice an open door policy. This includes the IEEE EMBS; the International Federation of Medical and Biological Engineering (IFMBE); and the European Alliance for Medical and Biological Engineering and Sciences (EAMBES).

Prof Christopher James, Professor of Biomedical Engineering, IEEE EMBS ADCOM (Europe Representative), IEEE EMBS UKRI Chair, IEEE Spokesperson in Europe for Healthcare Technology, Director of Warwick Engineering in Biomedicine. Dr Leandro Pecchia, Assistant Prof of Biomedical Engineering, Chairman of the Health Technology Assessment Division of the International Federation of Medical and Biological Engineering (IFMBE), Chairman of the Public Affairs Working Group of the European Alliance for Medical and Biological Engineering and Sciences (EAMBES).

1 WHO web site, last access 26th of October 2015,http://www.who.int/medical_devices/support/en/

2 EUR-LEX, 2015/C 291/07: EUR-LEX, 2015/C 291/07, “Opinion of the European Economic and Social Committee on Promoting the European single market combining biomedical engineering with the medical and care services industry”, Rapporteur: Edgardo Maria IOZIA, Co-rapporteur: Dirk JARRÉ

3 CNN Money, last access 27th of October 2015, http://money.cnn.com/pf/best-jobs/2013/snapshots/1.html

 

Christopher James

Director, WEB

Leandro Pecchia

Lead, Applied Biomedical Signal Processing and Intelligent eHealth Lab

Warwick Engineering in Biomedicine (WEB)

School of Engineering, University of Warwick

Tel: +44 (0)24 7652 8193

c.james@warwick.ac.uk

l.pecchia@warwick.ac.uk

www2.warwick.ac.uk/fac/sci/eng/research/biomedical

New anti-infective drugs following a grand tradition

Nobel Prizes are normally awarded to scientists whose fundamental discoveries have had a major impact over a number of years in the particular field of scientific research. Just occasionally a Nobel Prize recognizes a discovery that has come directly to the consumer. From the point of view of a medicinal chemist, it’s notable that two good examples of this concern the Nobel Prize for Physiology or Medicine, not for chemistry. In 1988 the Nobel Prize was awarded jointly to Sir James Black, and Drs Gertrude Elion, and George Hitchings for their establishing ‘important principles for drug treatment’, which in practice meant the discovery of β-blockers (Black) and antibacterial agents (Elion and Hitchings). As I write the news has come through that this year the Nobel Prize for Physiology or Medicine has been awarded to William C. Campbell and Satoshi Omura for their discovery of the antiparasitic drug, avermectin, and to Youyou Tu for her discovery of the antimalarial drug, artemisin. In both cases, the clinically used products today are derivatives of the naturally occurring compounds that the Nobel Laureates discovered and are further telling examples of a tradition of drug discovery based upon compounds isolated from plants and microorganisms.

I don’t wish to imply that our research has the necessary requirements of Nobel Prize standing but these achievements and their ultimate recognition are both an encouragement and a validation of our efforts to provide new compounds to treat infectious diseases by modification of natural products to give selectivity and suitability for medicines. Our most advanced compound, MGB-BP3, is progressing well in phase 1 clinical trials in a formulation designed to treat Clostridium difficile infections. Our development partner, MGB Biopharma, has also developed an intravenous formulation for the treatment of other Gram-positive bacterial infections building upon basic science from the University of Strathclyde. MGB-BP3 is the first in a line of new anti-infective compounds that ultimately work by controlling gene expression by binding to the minor groove of DNA in the target organism, according to the best evidence we have. It’s one of a family of compounds that we call Strathclyde MGBs (S-MGBs).

We now have S-MGBs that are effective against a wide range of infectious organisms in particular Gram-positive bacteria and trypanosomes, the disease-causing agent of sleeping sickness. We’ve been able to make such progress and to create such an impact for several reasons. Firstly the S-MGB platform uses very flexible heterocyclic chemistry so that we can tune the properties of our compounds to target different pathogens whilst remaining safe for the infected host. Secondly, we have strong team-work between many academic colleagues in chemistry and biology at Strathclyde but also at the University of Glasgow. Thirdly, we’ve worked in partnership with MGB Biopharma; the company’s ability to raise funds in a difficult economic climate and to drive through the development programme for MGB-BP3 has been extraordinary.

The outcomes of our research are targeting problems equally important today as those that the Nobel Prize winners addressed when beginning their research. According to current plans, we should begin to see the impact of our compounds in 2018, assuming that clinical development continues successfully.

 

Prof Colin J Suckling OBE DSc FRSE

Research Professor of Chemistry

Department of Pure & Applied Chemistry

University of Strathclyde

Tel: 0141 548 2271

www.strath.ac.uk/chemistry

Metals in Biology: Elements of the Bioeconomy

element metal
Scientist dripping water sample on test glass, heavy metals analysis, laboratory

At the beginning of 2014 the UK Biotechnology and Biological Sciences Research Council (BBSRC) established thirteen Networks in Industrial Biotechnology and Bioenergy. 1 An aim of these networks is to reduce the barriers for initiating collaborations between the academic and business communities, especially in the arena of Industrial Biotechnology. One of the networks entitled “Metals in Biology: The elements of Biotechnology and Bioenergy”,2 has seven themes: Metals in bioprocessing, metals in the environment, metal related nutrition and supplements, metallo-enzyme engineering, tools for metals in biology, metal circuits for synthetic biology and metal-related antimicrobials. Here this network is introduced, giving background to two themes with events planned this year.

Metals are used as industrial catalysts to drive reactions that produce valuable chemicals. Metals also catalyse a substantial proportion of the reactions of life.3 Using cellular enzymes whose structures are known as a representative sub-set, nearly a half (47%) of enzymes are estimated to need metals. The proportions of the individual elements which make-up this surprisingly large fraction. A second key observation is that metal-requiring enzymes readily bind to wrong metals in preference to the metals needed for activity.4 This creates the potential for enzymes to become inactivated by mismetalation. In this respect, life seems perilously ill-designed, but in truth, it has not been designed at all, rather it has evolved in the face of changing metal supply. This has selected for ‘circuits’ to assist proper enzyme metalation. Over the past three or more decades, many of the genes encoding components of these circuits have been discovered: Genes that encode proteins which import specific metals into cells, others which export, store or deliver metals and yet more which sense metal sufficiency or deficiency.4 These discoveries now create opportunities to engineer metal-circuits to enhance the metalation of desirable enzymes to the benefit of industrial biotechnology. Although beyond the scope of industrial biotechnology, this knowledge also makes it possible to study how these circuits fail in numerous chronic diseases and to devise ways to subvert metal circuits to eliminate unwanted cells for therapeutic purposes. As an aside, a common observation from the BBSRC NIBB is that fundamental knowledge of life processes tends to spark innovation across the entire bioeconomy including biomedicine, bioenergy, agrotechnology, nutrition, health, ecosystem management and not solely restricted to one sector such as industrial biotechnology.

Metal circuits for synthetic biology: Isobutanol is an industrial feedstock which is typically manufactured from fossil fuels. It can also be made biologically through the action of enzymes such as Dihydroxy Acid Dehydratase (DHAD)5. In many organisms, this enzyme uses iron in the form of iron-sulfur clusters and cells have specialised machinery for assembling and distributing these clusters.5,6 To generate a commercial fermentation process for the sustainable production of isobutanol, DHAD has been engineered into yeast cells. Patents document how the iron-sensing circuitry of yeast can be adjusted to ensure a sufficient supply of iron-sulphur clusters to support the extra demand created by the introduced DHAD5. With so-many enzymes needing metals, this exemplifies an opportunity to engineer wide-ranging metal circuits in order to enhance metalation of chosen enzymes to boost targeted reactions in support of the bioeconomy. For example, key enzymes required for the capture and utilisation of C1-gases (carbon dioxide, carbon monoxide and methane) have exotic metal demands including the nickel-containing F430 cofactor and cobalt in vitamin B12. Later this year, there will be a joint event between the Metals in Biology and the C1Net BBSRC NIBB7 to consider improving C1 gas capture by manipulating metals.

Metal-related antimicrobials:

Historically, some unpleasantly hazardous metals have been used to treat infections such as mercury for syphilis, arsenic and antimony for Leishmania. In agriculture, copper sulphate in Bordeaux mixture is an effective fungicide for treating vines, and hospital trusts have replaced steel fixtures and fittings with copper ones since copper surfaces (unlike those containing iron) are antimicrobial barriers. A range of products contains metal chelants such as Ethylene Diamine Tetra Acetic acid (EDTA) with preservative, antimicrobial, action. A well- known shampoo, which generates multiple billions of dollars of revenue each year, contains Zinc Pyrithione (ZPT) which interferes with the iron handling circuitry of fungi through a cunning sequence of biochemical interactions which also involve copper.8 ZPT treats dandruff which is triggered by the fungal microflora of the scalp. But there is a much longer history of using metals to fight microbes because immune systems have evolved to exploit metals to combat infections. This is emerging as a new sub-discipline called nutritional immunity.9

Iron often limits life, from restricting primary productivity in the oceans to the most prevalent human dietary deficiency, anaemia.10,11 Microbial pathogens fight to obtain this valuable element from hosts, often releasing iron scavenging siderophores. This has triggered an evolutionary arms race fought on a battleground of iron, with hosts producing defensive siderocalins to bind siderophores, in turn selecting for stealth siderophores which the siderocalins fail to recognise, combatted by stealth siderocalins from adapted hosts and so on. Host immune cells such as macrophages engulf microbes whereupon a specialised protein, Natural Resistance Associated with Macrophage Protein 1 (NRAMP1), helps to kill the entrapped invader. Some years after its discovery, NRAMP1 was found to pump vital metals such as iron from the microbe containing compartment, presumably to starve it of essential elements. The compartment subsequently fills with a toxic dose of copper. Calprotectin is liberated from other immune cell types, classes of neutrophils, to scavenge zinc and manganese, starving microbes of these essential elements.

As details of the cell biology of metals are uncovered, it becomes possible to tailor more precise antimicrobial treatments by design, not just stumbled upon empirically or by evolution. Metals, and by implication chelants, ionophores, and agents that interfere with the metal-handling systems of microbes and hosts are increasingly recognised among the promising candidates for new antimicrobials.12 Another upcoming BBSRC NIBB event will highlight advances in understanding metal-handling systems of microbes and hosts, explore why metals are a microbial “Achilles heel”, and encourage innovation at this academia-business interface.

 

1 http://www.bbsrc.ac.uk/about/institutes/nibb/

2 http://prospect.rsc.org/MiB_NIBB/

3 Nature (2009) 460, 823-830.

4 J Biol Chem. (2014) 289, 28095-28103.

5 http://www.gevo.com/about/our-business/intellectual-property/

6 Nature (2009) 460, 831-838.

7 http://www.c1net.co.uk/

8 Antimicrob Agents Chemother. (2011) 55, 5753–5760.

9 Nature Reviews Microbiology (2012) 10, 525-537.

10 Nature Geoscience (2013) 6, 701–710.

11 Nature (1999) 397, 694-697.

12 Nature (2015) 521 402.

 

Prof. Nigel J Robinson

Director

Metals in Biology BBSRC NIBB

metals.bbsrcnibb@durham.ac.uk

http://prospect.rsc.org/MiB_NIBB/

www.twitter.com/metalsbbsrcnibb

What’s so special about STEM?

Gill Collinson, Head of the National STEM Centre highlights the significance of STEM in modern life

‘STEM’ is the buzz word of the moment in education. Secretary of State for Education, Nicky Morgan, summed it up last year 1 when she said: “the subjects that keep young people’s options open and unlock doors to all sorts of careers are the STEM subjects: science, technology, engineering and maths.” With a huge push in business, government and education to move STEM to the top of the agenda, you might be asking – what’s so special about STEM?

It touches almost every aspect of modern life. Britain has always been at the forefront of ingenuity. Some of the most significant discoveries of the past 100 years were made in the UK. Britain started the Information Age, following on from our invention of the telephone and television with the World Wide Web, which now underpins almost every aspect of modern life. Huge leaps in medical science would not have been possible without the British discovery of penicillin or the structure of DNA.

The UK’s STEM industries also pack a punch. In ‘The state of engineering’ 2, Engineering UK reports that in 2014, the engineering sector contributed an estimated £455.6bn, the space sector contributed £9.1bn and the information technology sector £66bn to the UK economy. The numbers of job opportunities being created in STEM industries over the next decade will be huge. The United Kingdom Commission for Employment and Skills (UKCES)’ Working Futures’ model predicts that over 14 million jobs will need to be filled between 2012 and 2022. This is as a result of predicted growth in some sectors and occupations, however much of the need is as a result of people leaving the workforce, getting promoted or retiring, with most ‘hard to fill’ vacancies looking for people with strong STEM knowledge and skills.

In their 2014 Education and Skills report, ‘Gateway to Growth’ 3, the CBI highlighted the importance of STEM skills and excellent career advice in continuing to support these burgeoning industries. They predict a 52% rise in demand for highly skilled workers in engineering, science and hi-tech industries. Indeed, both the CBI and Engineering UK warn of dire economic consequences if we don’t meet the demand for the number of skilled individuals required in our STEM industries. Engineering UK predicts that failure to meet these skills demand could cost the UK £27bn a year.

The government is putting the building of strong STEM skills and industry in the UK at the heart of its economic plan for the UK. In July this year, Jo Johnson, Minister for Universities and Science, announced One Nation Science 4, a diverse program intended to boost research, skills and jobs in STEM across the UK. As part of this scheme, £67m has been set aside to find an extra 2,500 maths and physics teachers in the next 5 years, as well as to provide additional training for 15,000 existing maths and physics teachers. At the National STEM Centre, we support teachers across the UK with training and access to free, high-quality resources, to ensure they have everything they need to go out and inspire their students. The Your Life campaign 5, another government initiative, aims to increase participation in maths, with an ambitious target to increase the number of students taking maths and physics at A level by 50% in 3 years.

In the fast-paced, global economy we need our young people to have world-class education if we’re to stand a chance of keeping up. So why are STEM skills and industries so important? It’s clear that the UK’s future economic success and competitiveness depend on rebalancing the economy and, as part of this, expanding our knowledge-intensive industries with high levels of productivity and innovation. We need to continue to improve the STEM skills of the workforce in order to expand sectors such as advanced manufacturing, the digital and creative sectors and green businesses, all of which are underpinned by high-level STEM skills. By investing in STEM and our young people, we will remain at the cutting-edge of new technology, pioneering new science and at the forefront of ground-breaking discoveries. From building coding skills into the primary curriculum to educating young people on the benefits of following a STEM career, we have made much progress – but there is more still to do.

Gill Collinson joined the National STEM Centre in 2014 from Siemens Energy. Gill is a Chartered Engineer and has worked across both the private and public sectors.

The National STEM Centre works with schools across the UK to support excellent STEM education. www.nationalstemcentre.org.uk.

1 https://www.gov.uk/government/speeches/nicky-morgan-speaks-atlaunch-of-your-life-campaign

2 http://www.engineeringuk.com/EngineeringUK2015/EngUK_Report_2015_Interactive.pdf

3 http://www.cbi.org.uk/media/2807987/gateway-to-growth.pdf

4 https://www.gov.uk/government/speeches/one-nation-science

5 http://yourlife.org.uk/

 

Gill Collinson

Head

The National STEM Centre

www.nationalstemcentre.org.uk

China to the UK: Tackling cancer across borders

cancer
Fake Dictionary, Dictionary definition of the word cancer.

The China-United Kingdom Cancer (CUKC) Conference 2015 welcomed approximately 200 experts, including senior medics, scientists and scholars from world leading, international institutions to discuss strategies to fight cancer. The two-day event invited presentations from leading scientists and clinicians on effective cancer prevention, early diagnosis, aggressive treatment and rehabilitation recovery in basic and translational research, clinical treatment and research transformation. The thought-provoking sessions provided delegates with an opportunity to listen to scientific breakthroughs, learn from knowledge exchange and debate current challenges in cancer research. The sessions were complemented by exhibitions from industry sponsors and a display of approximately 100 research posters, for scientific discussion.

The highly prestigious event was jointly hosted by Cardiff University, Peking University, Capital Medical University (CMU) and Yiling Group, together forming the Cardiff China Medical Research Collaborative (CCMRC). The conference opened with addresses from international keynote speakers including First Minster of Wales, Carwyn Jones, Cardiff University’s President and Vice-Chancellor, Professor Colin Riordan, Peking University Cancer Hospital and Institute’s President, Professor Jiafu Ji, Professor Xiaomin Wang, Vice-President, Capital Medical University (CMU) and Mr Shen Yang, Minister Counsellor for Education, Chinese Embassy in UK.

Speaking at the welcome address ceremony at the National Museum, Cardiff, First Minister of Wales Carwyn Jones said: “It is a delight to see the impact of partnership working across international borders where institutions are joined by a shared ambition and willingness to tackle cancer; this fits with our over-arching policy framework in Wales called ‘together for health.’ A diagnosis of cancer is a major event in the lives of increasing numbers of people. There has been considerable progress in cancer care in Wales over the past 12 months. Working together against cancer, we can do even more.”

The conference’s co-chairmen, Professor Lu, President of Capital Medical University and Professor Ji, President of Peking University Cancer Hospital and Institute expressed their views of the event: Professor Lu said: “CUKC facilitates and deepens the collaboration between China and the UK. The event provides a worldwide, influential academic platform for oncology research,” with Professor Ji adding, “Cancer is a key health issue in China, UK and worldwide. This conference brings together like-minded experts to address these enormously resource consuming challenges which are beyond any single institution or country’s capacity.”

Key outcomes from CUKC 2015

Research platforms

The new platforms are in addition to ongoing joint projects in gastric, colorectal and pancreatic cancer: – – – – Lung Cancer Platform between Peking University, CMU and other UK institutions. The collaboration was a direct result of the CUKC 2015 Lung Cancer session

– Liver Metastases Platform between Cardiff, Oxford and Liverpool University, Peking University, CMU and Teaching Hospitals in China

– Ovarian Cancer Platform between Cardiff University, Peking University, Chongqing University. This platform will complement the existing relationship between the institutions and strengthen the China/Wales link

– Brain Tumour Platform. This was identified as a new priority and a framework is being drafted

Education

CUKC 2015’s poster display provided a developmental opportunity for the next generation of researchers. Scholars and scientists were welcomed to submit their abstracts for poster consideration and present over the two days.1 Honorary Chair of the Scientific Committee, and Nobel Prize Laureate Sir Martin Evans said, “It is wonderful to see the outstanding quality of the posters exhibited.”

Innovation

Yiling Group are in the final stages of licensing Cardiff University’s cancer technology which will lead to further opportunities in the future.

International engagement

CUKC 2015 also provided an opportunity to reflect on the collaborations successes to date, specifically the exchange of scholars and students which has accelerated since the launch of CCMRC in 2014.

Director of CCMRC, Professor Wen G. Jiang, said: “CUKC 2015 showcased past successes and refocused future priorities. The attendance by senior officials and leaders in the field of cancer research shows the importance attached to cancer research across the world. We will continue to expand our links with China and look forward to expanding the exchange programmes in 2016.” CUKC 2016 will be held in the Beijing National Convention Centre from the 13th-15th May. The four partners will continue to fight cancer together through the international collaborative.

CCMRC, which is based in Cardiff University’s School of Medicine, represents an internationally renowned cancer research team. The vibrant research community has supported a number of projects, resulting in the creation of several spinout companies. As well as providing opportunities for research, CCMRC supports the educational development of junior researchers and academics, including undergraduate and postgraduate students and clinical fellows, through teaching activities, research student – ships and clinical fellowships. The collaboration enables the four partners to undertake large-scale research, education and trials in cancer and in other areas of medicine. Over the past year, awards have included: China-UK Cancer Research International Collaboration Base (Beijing) with CMU, Key Laboratories of Cancer Invasion and Metastasis with CMU, awarded by the Beijing Government and the successful award of Natural Science Foundation research grants

1 Abstracts from the conference were published in the International Institute of Anticancer Research (IIAR), Anticancer Research July 2015 vol. 35 no. 7 4283-4369 and are also available on Highwire Press: http://ar.iiarjournals.org/content/35/7/4283.full.pdf+html Written by Ceri Frayne, Executive Officer, Cardiff China Medical Research Collaborative (CCMRC), Cardiff University, and Professor Wen G. Jiang, Dean of International, Director Cardiff China Medical Research Collaborative (CCMRC), Cardiff University

 

Cardiff China Medical

Research Collaborative

Cardiff University

Tel: 029 2068 7065

cardiffchina@cardiff.ac.uk

CUKC: www.cukc.org.uk

CCMRC: www.medicine.cf.ac.uk/cardiff-china/

Flying the flag for cancer research

OAG highlights the efforts made by the Welsh Government to improve cancer care and research throughout the country

Due to an ageing population, the demand for cancer care is ever increasing. In Wales, cancer is one of the two biggest causes of premature death, which is why tackling the disease is a top priority for the Welsh government. In 2014 1 they reported that the nation was spending more on cancer care, than ever before.

Figures revealed by the government highlighted that the total spend on cancer care had increased from £356.8m in 2011-12, to £360.9m for the year 2012-13. At the time, Minister for Health and Social Services Mark Drakeford said that the investment was made in clinically effective cancer treatments, which have a proven evidence base.

Speaking about the figures back in 2014 2, Drakeford said: “I’m determined to ensure every patient in Wales gets the best quality care they need and deserve. These figures show we are now spending more than ever on cancer care in Wales.

“This demonstrates our absolute determination to invest in health services that deliver the very best outcomes for the people of Wales. This means investing in medicines which are proven to work. I have consistently rejected calls to establish a cancer drug fund in Wales. To do so would prioritise cancer over other life-threatening conditions and divert money away from medicines which are proven to work.”

A new report ‘Together for Health – Cancer Delivery Plan (add link) reveals that more people in Wales are surviving cancer, even though the number of people diagnosed has risen. Between 1995 and 2011 there believed to have been on average, around 16,400 new cases of cancer every year in Wales. By 2012 that had risen to more than 18,000. The report also revealed that among people aged under 75, there was a 25% reduction in mortality rates between those same years. It also stated that since 1995, there has been a 17.5% improvement in the number of people alive one year after diagnosis and a 20.1% improvement in the 5-year survival rate.3

As one of the government’s key aims is to reduce the incidence of cancer throughout the nation, improving services is integral to this. In February last year, Mark Drakeford spoke to Assembly Members 4 about his plans for improvements in cancer care.

“Cancer is about more than ‘waiting times’,” he said. “It is about people and their care. In our recent Cancer Patient Experience Survey, I was pleased to see that so many people rate their care highly.” Published in 2014, the Cancer Patient Experience Survey was run in partnership with Macmillan Cancer Support and asked patients to rate their experience and provide feedback on the care and treatment they have received. Over 7,000 cancer patients were surveyed for the report, and it highlighted areas of care which needed improvement.

“The clear message of the survey is the majority of people receive excellent care and support in a wide range of areas,” said Drakeford.

“The survey did not just concentrate on medication or surgical procedures. It considered the whole journey faced by a person, starting when they are first given a diagnosis of cancer. I am pleased to report that 85% of people said they were always treated with respect and dignity by staff; 87% had confidence and trust in the doctors and nurses caring for them and 94% said they had enough privacy when being treated.

“I was very pleased to learn that Wales has the biggest increase in cancer survival rates in the UK. While our cancer survival improvement has been the best in the UK, we are still to reach the levels achieved in a number of other European countries. We need to continue to make progress here.” 5

As well as cancer care and treatment, Wales is home to one of the UK’s leading centres for cancer research at Cardiff University. The university has recently joined up with a number of Chinese universities to work collaboratively in the field of medical research, particularly cancer research.

Research at the university has played a major collaborative role in a multi-disciplinary, international effort to understand the molecular basis, diagnosis, prevention and treatment of cancer. This has led to long-term survival rates in the UK doubling over the last 40 years.

  • Around £5m has been invested into the Cardiff University-Peking University Cancer Institute 6, in order to support pre-clinical translational research. Through the Cardiff Cancer Collaborative, they hope to maximise the benefits to patients with 5 key areas of research strength:
  •  Tumour and environment;
  • Drug discovery, development and delivery;
  • Cancer immunology;
  • Personalised cancer genetics (and other translational research);
  • Clinical trials (and other clinical interventions).

The approach taken by the Cardiff Cancer Collaborative brings together all facets of cancer research activity in a United hub of expertise under a single strategy.

Further investments have been made, including £3m for the European Cancer Stem Cell Research Institute. Wales continues to make strides in its aim to tackle cancer and play a central role in cancer research. They may only be a small nation, but they are certainly off to a great start.

1 http://gov.wales/newsroom/healthandsocialcare/2014/140611cancer/?lang=en

2 IBID

3 http://gov.wales/newsroom/healthandsocialcare/2015/150114cancer/?lang=en

4 http://gov.wales/about/cabinet/cabinetstatements/2014/cancerservices/?lang=en

5 IBID

6 http://www.cardiff.ac.uk/research/explore/research-topics/biomedical-and-life-sciences/cancer

OAG

Open Access Government

Gynaecological cancers –prevention and early detection

Murat Gultekin, Vice-President of the European Society of Gynaecological Oncology (ESGO) highlights the importance of early detection of gynaecological cancers for prevention

According to World Cancer Report 2014 (IARC), at least one third of cancers are preventable. This is true for gynaecological cancers, especially cervical cancer. However, less than 5% of the whole cancer control budget in the EU is spared for prevention. A great majority of the total budget is still spent on treatment of cancer and only 25 of the 28 EU member states have a strategic cancer control plan.

Based on the UN General Assembly Resolution in 2011, cancer control and prevention will be the main focus for all countries within the next decade. New data estimates that the $18bn increase in funding per year by the international community could result in a 30% reduction in cancer deaths in low and middle-income countries by 2030.

In this respect scientific and non-scientific societies including ESGO have initiated new awareness campaigns. ESGO is the principal European society of gynaecological oncology contributing to the study, prevention and treatment of gynaecological cancer which also organises state of the art symposiums to upgrade the knowledge and skills about the highlighted topics, via the world’s most famous experts. In order to lead in several gynaecological cancers prevention, ESGO has decided to organise a 2016 symposium focusing on the prevention of gynaecological cancers, with specialised lectures on primary, secondary and tertiary prevention of cervical, endometrial, breast and ovarian cancers. In addition to the up to date scientific reviews, this meeting will also give an opportunity to reach and train all relevant groups such as cancer patients, their relatives and the young generation of European doctors. With almost 30 worldwide famous scientists, lecturers and 500 attendees from all around Europe and the Middle East Region, the 2016 ESGO State of Art Symposium- Antalya/Turkey will be a trademark and a cornerstone on gynaecological cancer prevention strategies.

Cervical Cancer

Cervical cancer is the 4th most common cancer of women around the world. Although it is a preventable, 2 women every 1 hour in the European Union, currently lose their lives because of this type of cancer. HPV is the main causative agent of cervical cancers and more than 70% of these cancers are related to HPV type 16 and 18. This is important because it means that a great majority of these cancers can be prevented via HPV vaccination and cancer related deaths can be avoided by early diagnosis through screening.

HPV Vaccination

Cervical cancer can be prevented and this can begin from childhood. We can save our children’s lives by vaccinating our children and avoid at least 3 out of 4 deaths by an effective HPV vaccination. These vaccinations are FDA approved, effective and safe vaccines, against to known oncogenic HPV types. Unlike most other vaccines, which are administered to children under the age of 5, HPV vaccines are inoculated to girls aged 9 to 13.

In contrast with the fact that HPV vaccines can prevent every 4 of 5 deaths from the cervical cancer and don’t have serious side effects, vaccination rates are still low around the world. According to VAERS (Vaccine Adverse Event Reporting System) about 92% of the side effect reports were classified as non-serious. The most common side effects are; injection problems, fever, headache, nausea and muscle or joint pain. Despite speculations the vaccine was found to not have any relation to a risk of multiple sclerosis in many scientific studies.

Screening

Besides prevention, early detection by screening still remains important. Population based, effective and well-designed screening programs should be the goal of achievement for all countries in a view of public health. In addition to the ongoing cytology programs, countries have many different screening strategies such as VIA/ VILI/ HPV DNA or a combination of all. Recent evidence shows HPV DNA can be safely used alone for cervical cancer, with its high scientific value and scientifically proven success.

Uterine Cancer

The most common type of uterine corpus cancer is endometrial cancer, which is the 5th most common cancer of women in the world. It is mostly symptomatic and could be easily diagnosed and totally curable at early stages. It is generally seen after the menopause with only 5% of the cases under 40 years of age. Most of these cancers are related to obesity and high oestrogen exposure. There aren’t any feasible and acceptable screening methods for endometrial cancer, however it is important to be aware of the fact that any postmenopausal bleeding may be an early sign of it.

Ovarian Cancer

Ovarian cancer is the 7th most common cancer among women in the world and it is the most deadly gynaecologic cancer. Although there are not any adoptable screening methods for this cancer at a community level, it is curable if diagnosed in the early stages. It is important to raise public awareness about the symptoms of ovarian cancer so it can be detected earlier. There is also a genetic proportion of this cancer but only 10% of ovarian cancer cases have this liability. Women who have a family history of ovarian, endometrial or colorectal cancer could be screened for genetic predisposition and be prevented by some measures. There are many studies on ovarian cancer which may lead screening and early diagnosis or new treatment options.

Conclusion

More than 70% of gynaecological cancers can be prevented and the harm caused by them can be reduced by several measures such as screening and vaccination programs. It is important to be aware of first the importance of prevention then the importance of early diagnosis. In conclusion; “Raising Awareness” should be our first as this is the most important initial point for saving more people’s life.

Murat Gultekin, MD, Assoc. Professor

Vice-President – ESGO

IARC Governing Council Member

Director

Cancer Control Department

Turkish Ministry of Health

www.esgo.org

Research at Oslo University Hospital in the field of Gynaecologic cancer

Gynecologic cancer
Gynecologic cancer word made of square letter word on pink background.

Oslo University Hospital (OUS) is a big hospital formed by the merger of 4 hospitals. The State Hospital, the Norwegian Radium Hospital, Ullevaal Hospital and Aker Hospital. It serves as a local hospital for about 600,000 inhabitants and as a referral centre for about 2.8 million people. As a big University center, OUS is heavenly dependent on research and development.

In the field of gynecologic oncology, we are engaged in international clinical trials and in more basic research, but also in refinements of diagnostic and therapeutic procedures.

In the field of international clinical trials, our department has participated in some important studies on ovarian cancer. Standard treatment for ovarian cancer is surgery, if the patient is fit, followed by chemotherapy. The goal for surgery is to remove all visible tumour elements. The ICON7 trial showed a benefit of adding bevacizumab to chemotherapy for patients with a high risk of relapse. This group consisted of patients with residual tumour of 1 cm or more after surgery for ovarian cancer or stage 4. The patients received bevacizumab together with standard chemotherapy, followed by maintenance treatment with bevacizumab for a total treatment period of 12 months. For the high-risk group, survival was prolonged by 4.8 months from 34.5 to 39.3 months. The length of the maintenance phase in the ICON7 study was chosen somewhat arbitrarily. It is a question whether the maintenance phase should be extended until the progression of the tumour. This is the basis for an ongoing study (OVAR17), for which we do not yet know the results. Another important study is the Calypso study on relapsed ovarian cancer resistant to standard carboplatin-based chemotherapy. Patients were randomized to either chemotherapy or chemotherapy and bevacizumab. The treating physician could choose between 3 commonly used chemotherapies. This study showed a prolongation of the median time to relapse from 3.4 with chemo alone to 6.7 months with chemo and bevacizumab. Survival was somewhat, although not statistically significant, increased from 13.3 to 16.6 months. The addition of bevacizumab was very effective in treating ascites, which can be very troublesome for this group of patients.

Some 10-15% of patients with ovarian cancer have a defect in the BRCA genes. This defect is heritable. Our department offers free testing of the BRCA genes to all patients with ovarian cancer. In the case of a defect gene, the patient can then pass this information to her children. Knowledge about the status of the BRCA genes also has implications for the treatment of the patient. In a previous study (Lancet Oncol. 2014 Jul;15(8):852- 61) it was shown that maintenance treatment with Olaparib (a PARP inhibitor) prolonged the median time to progression by 6.9 months from 4.3 to 11.2 months in patients having a BRCA defect tumour. The patients received maintenance treatment with Olaparib after having chemotherapy for a relapse of ovarian cancer occurring 6 months or later after previous platinum-based chemotherapy. We participated in studies on another PARP inhibitor to further evaluate the effect of these drugs after the initial treatment and after later relapse.

For families with a defect BRCA gene, this implies a considerable burden. The women in the family have to decide whether they want to test the status of their gene. In case of a defect gene, they have to decide whether they prefer risk-reducing surgery by removing the ovaries and fallopian tubes at the age of 35-40 years. The psychologic stress, effect on the quality of life and also somatic side effects have been the topic for a recent PhD study from our department.

In the department for pathology at our hospital, Professor Ben Davidson and his colleagues have done a tremendous job by evaluating the importance of a number of genes for resistance to chemotherapy. Detailed knowledge about the biology of tumours is important for drug development. In some cases, the treatment for each individual patient can also be guided by knowledge about the biology of the patient’s tumour.

For some tumours, important signal pathways in the tumour are already known. In well-differentiated serous ovarian cancer, the MEK pathway is such an example. We participate in a study to evaluate the effect on survival by blocking the MEK pathway.

Immunotherapy has become much in focus in recent years after the successful first obtained in malignant melanoma and later on in other tumour forms.

Studies in gynaecologic cancer on checkpoint inhibitors have just started. Our department participates in a couple of phase II studies and a phase III study is in development.

In cervical cancer, the 5-year survival in Norway is about 78%. There are a number of reasons for this high survival rate such as the effect of screening on stage distribution, living conditions and the quality of health care. In our department, we have used a lot of resources in research and development on treatment aspects of cervical cancer. The delineation of the tumour and metastases is important for good treatment planning. We use DCE-MRI routinely for this purpose. It has for some time been well known that hypoxia in the tumour decreases the susceptibility to radiation. Detection of hypoxic tumours or hypoxic parts in the tumour might, therefore, be of clinical relevance by either increasing the dose of radiation to these parts of the tumour or by administering some drug that could increase the sensitivity to radiation of these hypoxic tumour cells. Researchers in our institution has found that, by texture analysis of pictures obtained by DCE-MRI, they could predict the outcome for the patient. Other researchers have worked on the importance of genes and their expression in cervical cancer. They have developed and validated a gene list identifying hypoxic tumours. This list has been compared to the findings by texture analysis of DCE-MRI and they fit together. This can be used to select patients for studies on the effect of drugs with special effect on hypoxic cells given alongside radiotherapy.

 

Gunnar Kristensen

Professor, Consultant, PhD

Oslo University Hospital, Radiumhospital

Tel: +47 22934000

gbk@ous-hf.no

www.oslo-universitetssykehus.no/

Improved cancer care: Integrating palliative care and oncology

Norwegian cancer researchers launch a project to improve care for cancer patients with a limited life expectancy

Europe has about 3.5 million new cancer cases per year, and the number is rising. Advances in treatment options have led to more patients getting cured and prolonged survival for those with incurable disease. However, a major concern in cancer care is the rapidly increasing complexity of treatment, which leads to escalating costs threatening the sustainability of the services. One important contributor to this scenario is the increasing use of chemotherapy during the patient’s last year of life – often without documented efficacy.

Patients receiving intensive oncologic treatment during their final months or weeks have a poorer quality of life than those who receive symptom-directed treatment. Indeed, recent studies show that introducing a palliative care approach at an early stage in patients with the incurable disease may improve their quality of life and even prolong survival.

PALLiON

In 2014, Norway’s four Regional Health Authorities announced a call for cross-regional research projects to strengthen clinical research and health services research. The program was administered through the Research Council of Norway, and cancer research was one of the prioritized areas.

Against the backdrop described above, leading researchers in oncology and palliative care submitted a proposal to test the efficacy of an intervention integrating oncology and palliative care services for cancer patients with a life expectancy of less than one year – PALLiON. The proposal was highly ranked and received €3 million (25 million NOK) funding for a five-year project. PALLiON was the only cancer-related study to be funded within this call.

Collaborative effort

PALLiON is designed as a national, multi-centre, cluster-randomized trial. This means that the intervention is performed at an institutional level, with six hospitals forming the ‘active cluster’ in which the intervention takes place. Six matching hospitals constitute the ‘control cluster’. The 12 hospitals have been recruited from all health care regions in Norway and range from small, local hospitals to large university clinics. A total of 550 patients who are receiving chemotherapy and have a life expectancy of less than one year will be included in the study.

PALLiON will be coordinated from Oslo University Hospital, with Professor Jon Håvard Loge as Principal Investigator. The Project Management group has members from the University Hospitals in Bergen, Trondheim, and Oslo, supported by a distinguished international reference group.

Complex intervention

The intervention to be tested in the PALLiON study consists of three parts: Systematic electronic assessment of symptoms, implementation of an integrated care pathway, and an educational program for oncologists and palliative care physicians.

Pain, fatigue, loss of appetite and other distressing symptoms are common in patients with advanced cancer. Lack of a systematic assessment has been identified as one of the barriers to effective symptom control. In PALLiON, symptoms will be frequently and systematically assessed by means of EIR, a computer program developed at the European Palliative Care Research Centre (PRC) at the Norwegian University of Science and Technology in Trondheim.

The integrated care pathway gives an outline of the patient pathway, integrating oncologic treatment, palliative care and end-of-life care, and hospital as well as community care. The aim of the pathway is to promote early integration of the palliative care approach, and to reduce the variability in clinical practice.

The educational program is tailored to the other elements of the intervention but puts the main emphasis on communication, prognostication and symptom management.

Project goals

Combined, the three elements of the intervention are expected to improve symptom management, improve quality of life for the patients and their families, and empower them to play an active part in decision-making. We also hypothesize that the intervention will lead to reduced hospital stays and increased use of community-based care in the final months of life. The main outcome measure of the project will be the proportion of patients treated with chemotherapy in the last three months of life.

The detailed study protocol is under preparation. This also includes assessment of all study sites at baseline. A study organization has been set up at Oslo University Hospital, and interdisciplinary teams are working on the different elements of the intervention. Local study coordinators and groups are being established at all project sites.

Inclusion of patients will start in September 2016.

 

Dagny Faksvåg Haugen

Lead Consultant, Head of Centre, Professor of Palliative Medicine

Regional Centre of Excellence for Palliative Care, Western Norway,

Haukeland University Hospital, and Department of Clinical Medicine, University of Bergen, Bergen, Norway

Tel: +47 55 97 58 31

dagny.haugen@helse-bergen.no

www.helse-bergen.no/palliasjon

Reducing the burden of cancer

NCI

AG highlights the work of the National Cancer Institute (NCI), to reduce and treat cancer.

The National Cancer Institute (NCI) is the U.S. Federal government’s primary agency for cancer research and training. As part of the National Institutes of Health (NIH) they coordinate with the National Cancer Programme, which conducts and supports research, training, health information dissemination and other programs related to cancer – i.e. diagnosis, prevention, and treatment. Real progress is being made against cancer worldwide, and due to the work of NCI and medical researchers throughout the U.S., in 2012 there were approximately 14 million cancer survivors throughout the country.

The NCI estimated that in 2015, 1,658,370 new cases of cancer will be diagnosed in the U.S. and 589,430 people will die from the disease. Approximately 39.6% of men and women will be diagnosed with cancer at some point in their life, with breast, lung, bronchus, prostate, colon, bladder, melanoma of the skin and rectum cancer named the most common cancers in 2015. 1

Throughout the U.S. the rate of new cancers overall has been declining for more than a decade. Through new treatments and understanding for the detection and diagnosis, people living with cancer are living longer and with a better quality of life than ever before. In a blog post 2 by Acting NCI Director, Doug Lowy, M.D, he discusses the critical contribution of basic science in fostering progress against cancer.

“Over the past 2 decades, we have made significant progress in diagnosing and treating cancer- progress that is reflected in the continuing declines in cancer death rates and the increasing numbers of cancer survivors. This progress is only possible because of our efforts to understand the biological mechanisms underpinning cancer.

“When or where the next major advance in cancer research will occur is unknown, but it always begins with basic research – often in areas which a direct application to medicine may not be immediately apparent, including areas such as physics, mathematics and materials science.”

Ensuring people receive the right treatment for their cancer is integral to their quality of life. Treatments for cancer can come in many forms. Some people require a combination of measures, whilst others only have one type. The majority of people with cancer do have combination treatment, which could consist of surgery with chemotherapy and/or radiation therapy.

Treatments and new drugs are tested using clinical trials. Cancer patients at any stage of their treatment can take part in these, and they are key to developing new methods to prevent, detect and treat cancer.

Clinical trials can also bring to light new information and outcomes to researchers in regards to the cancer and the way it reacts to drugs. At NCI a clinical trial has recently revealed some interesting results in regards to precision medicine and the most common type of lymphoma.

Lymphoma is a cancer that begins in cells of the lymph system and can being almost anywhere in the body. The joint study conducted by the NCI, and Pharmacyclics Sunnyvale, California revealed that patients with a specific molecular subtype of diffuse large B cell lymphoma (DLBCL) are more likely to respond to a specific drug that patients with another molecular subtype of the disease. 3

Several years ago, NCI scientists identified two primary subtypes of DLBCL based on characteristic patterns of gene activity with the lymphoma cells. This discover led the researchers to believe that targeted treatments could be developed.

Louis Staudt from the NCI Centre for Cancer Genomics, who co-led the study, said: “Clinical trials such as this are critical for translating basic molecular findings into effective therapies.”

Study co-leader Wyndham Wilson of the NCI added: “This is the first clinical study to demonstrate the importance of precision medicine in lymphomas.”

Target therapy is the foundation of precision medicine and works by targeting the changes in cancer cells that help them grow, divide and spread. Most cancers patients will have a target for a certain drug, so they can be treated with that drug. However, most of the time the tumour will need to be tested to see if it contains markers for which we have drugs. Most targeted therapies help the immune systems destroy cancer cells; stop the cancer cells from growing; stop signals that help for blood vessels; deliver cell-killing substances to cancer cells; cause cancer cell death; and starve cancer of the hormones it needs to grow. 4

However, there are some drawbacks to targeted therapy, as there is with most cancer treatments. Cancer cells may become resistant to them and drugs for targets are hard to develop. With detailed research and funding, cancer treatments have come a long way over the years. However, the questions still remains: why haven’t we found a cure yet? Treatments available can extend life, and if caught at the right time many people do survive cancer. Due to the complicated nature of cancer and the number of types there are, it is still proving a difficult task to find that cure to eliminate this awful and life changing disease.

Organisations like the NCI play a pivotal role in getting us closer to finding that cure. Ongoing cancer research and clinical trials to test and develop new drugs could be that crucial step to help patients live a longer and happier life, with or without cancer.

1 http://www.cancer.gov/about-cancer/what-is-cancer/statistics

2 http://www.cancer.gov/news-events/cancer-currents-blog/2015/bypass-basic-science

3 http://www.cancer.gov/news-events/press-releases/2015/ibrutinib-lymphoma-subtype

4 http://www.cancer.gov/about-cancer/treatment/types/targeted-therapies

AG

editorial@adjacentopenaccess.org

www.adjacentgovernment.co.uk

Connecting the dots between physical and mental health

mental health

Ophelie Martin, Communications Officer at Mental Health Europe shares insights on the link between physical and mental health, illustrating facts with her own personal story.

According to the World Health Organization, “Health is a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity.” 1 The medical community has known for a long time that physical and mental health problems are intertwined, and that is why the global health community emphasises the mantra: there can be no health without mental health. Yet, as this article seeks to show, while this fact is known, it is not born out in practice by many health professionals as well as health care systems around the world.

We now know that people with long term physical diseases are twice as likely to have some kind of mental health issue. The prevalence of major depression is consistently higher for persons with physical illness, and yet, it has been estimated that while 25% of all individuals with cancer are depressed only 2% 2 receive treatment for depression. Researchers 3 have also found that mental issues are directly associated to a number of somatic diseases, such as asthma, pulmonary problems, musculoskeletal disorders (such as arthritis), neurological diseases and chronic pain conditions. The connection seems to be reciprocal: chronic somatic diseases often result in serious health problems and vice versa.

More alarmingly, people living with severe problems such as schizophrenia, major depressive disorder or bipolar disorder report poorer physical health in general and have shorter life expectancy than those without mental health conditions 4. These facts alone should encourage health professionals and decision-makers to address the link between mental and physical health more effectively.

Once people experiencing mental health problems are diagnosed with a certain condition, they tend to be labelled as “mentally ill” which can sometimes have unintended life-altering consequences. It must be acknowledged that the stigma around mental ill health is also experienced in today’s health care systems, because of lack of knowledge and appropriate training of health professionals on how to treat those affected by both mental and physical health problems.

Poor treatment or lack of treatment for physical health for those with mental health problems is a lived reality for many. My own personal story can illustrate how serious stigma against people with these problems within the medical community can drastically change their health prospects. My father, a 63-year old loving family man diagnosed with bipolar disorders and schizophrenia, went to his GP many times constantly complaining of severe stomach pain. His GP was aware of his condition and wrongly assumed the pain was linked to his mental health problems and as a result failed to examine him properly. A few months later, my father died from pancreatic cancer, in part due to the fact that it was not diagnosed in a timely fashion by his GP. His GP repeatedly reassured him that it “would get better”. I have asked myself this question over the years: would my father’s GP have treated a person without mental health problems, who had presented consistently with stomach pain, in the same manner? This is just one single example among other unacceptable and heart breaking stories from across Europe and beyond.

Research 5 has highlighted the ‘treatment gap’ for people with mental health problems – 9 out of 10 individuals’ experiencing mental illness worldwide are not able to access appropriate care and treatment. A recent Quality Watch Report 6 shows that too often a person’s mental health care is collected in isolation of their physical health care. This too often results in the physical health needs of people with mental health ill-health remaining unidentified. How can this treatment gap be addressed? What can we do to combat stigma and promote a better understanding of mental health?

Mental Health Europe believes that health is not only a medical concern but also a human rights issue. If the link between mental and physical health is not properly addressed then health systems cannot respond to the health needs of rights holders, thus depriving them of their right to the highest attainable standards of health as outlined in Article 12 of the UN Convention on Economic, Social and Cultural Rights.

To address the link between mental and physical health efficiently, a variety of training, educational and awareness-raising programmes targeted at health professionals, carers and volunteers in the community should be launched and supported by both national and EU financial instruments. To avoid additional health problems and misdiagnoses, greater investment in health promotion and disease prevention should be emphasised especially in the case of individuals who already have mental or chronic physical difficulties.

MHE is working together with members to ensure that mental health is high on the agenda at European and national levels, advocating for the human rights, social inclusion and access to healthcare of people with these problems. One in 4 people in the world will be affected by mental health problems at some point in their lives. Health systems must be prepared to address comorbidity of mental and physical ill-health as well as the treatment gap for persons with mental health problems. If some of the above actions, particularly training for health professionals, had been implemented when my father attended at his GP the very first time he felt that something was not right, the care he received could have saved his life.

Mental Health Europe is an umbrella organisation which represents associations, organisations and individuals active in the field of mental health and well-being in Europe, including (ex) users of mental health services, service providers volunteers and professionals. Mental Health Europe envisions a Europe where people with mental health problems live as full citizens with access to appropriate services and support, where positive mental health and well- being are given high priority in the political spectrum and on the European health and social agenda, and where meaningful participation is guaranteed at all levels of decision-making.

1 http://www.who.int/about/definition/en/print.html

2 http://www.researchgate.net/publication/5928479_Increased_12Month_Prevalence_Rates_of_Mental_Disorders_in_Patients_with_Chronic_Somatic_Diseases

3 http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0032190

4 http://www.mhe-sme.org/fileadmin/Position_papers/Study_on_the_interlink_between_mental_and_physical_health__July_2014.pdf

5 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2570037/

6 http://www.qualitywatch.org.uk/sites/files/qualitywatch/field/field_document/QualityWatch_Mental_ill_health_and_hospital_use_full_report.pdf

 

Ophelie Martin

Communications Officer

Mental Health Europe

ophelie.martin@mhe-sme.org

www.mhe-sme.org

Can we sustain an ageing population?

ageing

With people living longer, and health systems under strain, AG looks at the worldwide impact of an ageing population.

The World Health Organization (WHO) predicts that between now and 2050, the number of people over the age of 60 worldwide is likely to rise, from 11% in 2000 to 22%. The proportion of over 60’s is expected to increase from 605 million to 2 billion over the same period. The biggest concern with these figures is the detrimental impact an ageing population can have on our health systems.1

In November 2014, Dr John Beard, Director of the Department of Ageing and Life Course at WHO warned that, “Deep and fundamental reforms of health and social care systems will be required.” 2

As people reach age 75 and over, the risk of chronic diseases can increase. It is estimated that around 25-30% of people aged 85 or older will have some degree of cognitive decline, such as dementia. If we continue to see a rise in the number of people that can no longer look after themselves, it will have a huge bearing not only on social care services, but also the economy.

For the first time in history, it is predicted that by 2020 the number of people aged 60 or over will outnumber the number of children aged under 5. Worldwide expectancy will continue to rise with 80% of these older people believed to be living in low-income and middle-income countries, says The World Health Organization (WHO). The long-term challenges of illness and reduced wellbeing will not only affect the patient, but also their family. With forecasts predicted to accelerate, latest estimates indicate that the number of people with dementia is anticipated to rise further, from 44 million in 2014, to 135 million in 2050.

Dr Ties Boerma, Director of the Department of Health Statistics and Informatics at WHO said, “We must be careful that these reforms do not reinforce the inequalities that drive much of the poor health and functional limitation we see in older age.

“While some interventions will be universally applicable, it will be important that countries monitor the health and functioning of their ageing populations to understand health trends and design programmes that meet the specific needs identified.”

Dr Boerma added: “Cross-national surveys such as the WHO study on Global Ageing and Adult Health (SAGE), the Gallup World Poll, and other longitudinal cohorts’ studies of ageing in Brazil, China, India and South Korea, are beginning to redress the balance and provide the evidence for policy, but much more remains to be done.”

WHO believes that strategies are needed to help prevent and better manage chronic conditions that blight ageing populations. “Collectively, we need to look beyond the costs commonly associated with ageing to think about the benefits that an older, healthier, happier and more productive older population can bring to society as a whole,” added Dr Chatterji, also from the Department of Health Statistics and Information Systems at WHO.

Francesca Colombo, Head of the Health Division at the OECD told AG 3 that she believes an ageing population is “an opportunity,” and that we need “to take ageing as something to celebrate.” She believes that encouraging healthier lifestyles early in life can help to prevent the development of chronic diseases, and other disabilities. However she explained it is vital services do not become over stretched to help deal with the ageing population.

She said: “Health systems must adapt to changing patterns of morbidity and disease burden. Health systems across the OECD are still too much hospital focused and struggle to innovate approached to care for an ageing population.

“The way health systems have developed is more orientated towards the treatment of disease and dealing with acute episodes of care, rather than focussing on preventing ill health, managing chronic care needs and encouraging continuity of care.”

She added that GPs and primary care providers should play a more central role, working alongside community health and social care services.

WHO have launched a draft ‘Global Strategy and Action Plan on Ageing and Health’ 4 The Strategy aims to define the goals, strategies and actions that WHO will pursue, and to clearly lay these out for public health action. With the Strategy WHO aim to provide a comprehensive framework for action on ageing and health, identify gaps and suggest future priorities. Strategic objectives for the next 5 years are:

 – Fostering healthy ageing in every country;

– Aligning health systems to the needs of the older populations;

– Developing long terms care systems;

– Creating age-friendly environments;

– Improving measuring, monitoring and understanding.

The draft Strategy is currently open for consultation, and an updated version is to be presented to the WHO Executive Board in January 2016.

1 http://www.who.int/ageing/about/facts/en/

2 http://www.who.int/mediacentre/news/releases/2014/lancet-ageing-series/en/

3 https://www.openaccessgovernment.org/adapting-ageing-population-2/20387/

4 http://www.who.int/ageing/global-strategy/GSAP-ageing-health-draft.pdf?ua=1

 

AG

editorial@adjacentopenaccess.org

www.adjacentgovernment.co.uk

Citizens with mental illness are helped by tele-rehabilitation using video technologies

Citizens with mental disorder face a number of challenges returning to everyday life following discharge from psychiatric hospital. The citizens often feel insecure, anxious, and at risk of readmission rate to psychiatric hospital.

In Denmark, municipalities are offering support services for citizens with mental illness in their recovery process after discharge from hospital. Municipal social workers visit the citizens in their home from one time a week to several times a day, talk with them about feelings of insecurity and offer assistance in helping them structure their daily routine.

In 2013, the Danish municipality of Esbjerg began a research project focusing on tele-rehabilitation for citizens with mental illness, where video technology is used to facilitate improved dialogue between the citizens and their social worker. The aims of the research project are twofold: (1), to reduce readmission of the citizens to a psychiatric hospital, and (2), to prevent worsening of symptoms by giving the citizens the possibility to communicate virtually with a team of social workers on a 24/7 basis.

In the United States, tele-psychiatry has been a part of routine care delivery for citizens with mental illness for years. In Europe, however, tele-psychiatry is still not integrated into routine care delivery, and little research has been performed. The research project in Esbjerg Municipality is one of the first initiatives within this field in Europe.

The target group for the research trial are citizens diagnosed with depression, schizophrenia, paranoia and manic depression who have been discharged from hospital. The citizens receive video technology installed in their homes so that they can communicate with their social worker. Each citizen is assessed after having used the system for a period of 6-18 months. A total of 57 adult citizens have been included in the project: 30 females (mean age 35.3) and 27 males (mean age 39.7).

Preliminary findings from qualitative interviews with the citizens have shown that the video system had given the citizens a feeling of safety and security and helped them to develop new individual coping strategies to avoid admission to hospital.

The citizens stated that via the video technology, they could can get in contact with a social worker at any hour of the day, whenever they needed to talk about their feelings, heard voices or were having hallucinations. Some citizens diagnosed with paranoia, however, found it difficult to stand directly in front of the web camera for communication with the social worker. Instead, they chose to stand next to the camera when communicating with their social worker.

The social workers reported that the video technologies have improved their collaboration and communication with the citizens with mental illness. The video technology has been easy to use, and they report having saved time on transportation. The social workers reported that they can now tailor their intervention on a more individual basis and provide higher quality support to those citizens with mental illness.

“The preliminary findings from the project have shown positive results, and the next step will be to implement the system on a larger scale in Esbjerg Municipality during the coming years,” explains Britta Martinsen, CEO of Social Services in the Municipality of Esbjerg.

Esbjerg Municipality have started to plan to scale up the pilot project. They plan to integrate the video technology into the daily work routine for the social workers so that it serves up to 150 citizens with mental illness.

 

Claus Ugilt Oestergaard

Consultant for Assistive Technologies

Department of Citizen  & Labour Market, Esbjerg Municipality, Denmark

Tel: +4523279637

clast@esbjergkommune.dk

wwww.esbjergkommune.dkk

Drug development for Alzheimer’s disease

Alzheimer’s disease (AD) is a major problem of health and a national priority in developed countries. Despite enormous efforts by governments, the scientific community and the pharmaceutical industry over the past 50 years, no therapeutic breakthroughs have yet been achieved, and the drugs available for the treatment of AD are not cost-effective. In terms of costs, AD accounts for $226 billion/year in the USA and €160 billion/year in Europe (>50% are costs of informal care, and 10-20% are pharmacological treatment costs). It is estimated that in the USA alone the direct cost of AD in people over 65 years of age could be over $1.1 trillion in 2050 (from 2015 to 2050, the estimated medical costs would be about $20.8 trillion).

During the past 10 years, over 1,000 different compounds have been screened as candidate drugs for AD; there have been over 400 unsuccessful formal attempts to develop new drugs, and at present fewer than 100 clinical trials with AD-related drugs are in progress worldwide.

Recent data reported by Jeffrey L Cummings, Travis Morstorf and Kate Zhong (Alzheimer’s Research & Therapy 2014, 6:37) indicate that during the 2002-2012 period, 413 AD trials were performed (124 Phase 1 trials, 206 Phase 2 trials, and 83 Phase 3 trials) (78% of them sponsored by pharmaceutical companies). Registered trials addressed symptomatic agents (36.6%), disease-modifying small molecules (35.1%) and disease-modifying immunotherapies (18%), with a very high attrition rate (overall success rate: 0.4%; failure: 99.6%).

These numbers reflect that the pharmacological history of AD is a chain of repetitive failures. Potential reasons to explain this historical setback might be that: (i) the molecular pathology of dementia is still poorly understood; (ii) drug targets are inappropriate, not fitting into the real etiology of the disease; (iii) most treatments are symptomatic, but not anti-pathogenic; (iv) the genetic component of dementia is poorly defined; and (v) the understanding of genome-drug interactions is very limited. Therefore, there is an urgent need to improve these poor results, since the approval of a new disease-modifying drug by 2025, capable of delaying AD onset by 3-5 years, would reduce the prevalence of AD by 30% and, consequently, reduce the cost of AD in the USA at an estimated rate of $300-$400 billion/year by 2050.

The most important issue for efficient drug development and subsequent therapeutic intervention is understanding disease pathogenesis. AD is a complex disorder in which multiple defects distributed across the human genome, together with diverse environmental factors, cerebrovascular dysfunction, and epigenetic phenomena are potentially involved. Major AD-related pathogenic events include genomic and epigenetic defects which may lead to the phenotypic expression of extracellular Aβ deposition in senile plaques and vessels as the result of the abnormal processing of APP by secretases, intracellular neurofibrillary tangle formation due to hyperphosphorylation of tau protein, dendritic desarborization, synaptic loss, and premature neuronal death, accompanied by gliosis, microglia activation, neuroinflammatory reactions, ROS generation, neurotrophic failure, and neurotransmitter dysfunction. This cascade of deleterious events can be differentiated into primary and secondary pathogenic factors which can serve as candidate targets for drug development.

In addition to the drugs approved by the FDA since 1993 (tacrine, donepezil, rivastigmine, galantamine, memantine), most candidate strategies fall into 6 major categories: (i) novel cholinesterase inhibitors and neurotransmitter regulators, (ii) anti-Aβ treatments (APP regulators, Aβ breakers, active and passive immunotherapy with vaccines and antibodies, β- and γ-secretase inhibitors or modulators), (iii) anti-tau treatments, (iv) pleiotropic products (most of these of natural origin), (v) epigenetic intervention, and (vi) combination therapies.

Therapeutic setbacks with candidate AD drugs suffered during past decades might be valuable for researchers and for the pharmaceutical industry to identify wrong decisions and technical mistakes; however, they are very costly and disappointing, with negative consequences for future investments. Probably the most relevant problem in the development of novel drugs with potential anti-neurodegenerative effects is that neuronal death starts 30-40 years before the clinical onset of the disease, when brain maturation stops around the age of 30-35. When the first symptoms appear in the elderly, thousands of millions of neurons have already died, and there is no drug capable of inducing neuronal resurrection. Therefore, it is clear that an efficient treatment should be administered many years before the onset of the disease. This situation requires important conceptual changes in the management of AD and in the development of new drugs for this devastating disorder: (i) the development of preventive medicines; (ii) new regulations for the administration of preventive treatments; (iii) early identification of the population at risk with specific biomarkers; and (iv) development of preventive protocols (i.e. initiation time, duration, costs, evaluation of chronic effects, etc).

In the mid-term, the optimization of AD therapeutics requires the establishment of new postulates regarding (i) the costs of medicines (improvement in cost-effectiveness), (ii) the assessment of protocols for a multi-factorial treatment, (iii) the implementation of novel therapeutics addressing causative factors (primary targets), (iv) the setting-up of pharmacogenomics strategies for drug development, (v) the incorporation of pharmacogenomics and epigenetic protocols into the clinical setting (epigenetic changes are potentially reversible with pharmacologic intervention), and (vi) new regulations for the development of vaccines and/or other preventive strategies to treat susceptible patients in presymptomatic conditions.

The incorporation of pharmacogenomics and pharmacoepigenomics into drug development in preclinical stages and in clinical trials would bring about several benefits: (i) to identify candidate drugs for specific targets on a predictive basis (not relying on serendipity or trial-and-error assays); (ii) to reduce costs and time in preclinical studies; (iii) to identify candidate patients with the ideal genomic profile to receive a particular drug; (iv) to adapt the dose in over 90% of the cases according to the condition of CYP-related extensive (EM), intermediate (IM), poor (PM) or ultra-rapid (UM) metabolizer (diminishing the occurrence of direct side-effects in 30-50% of cases); (v) to ensure drug penetration into the brain (drug transporter geno-typing); (vi) to reduce drug interactions by 30-50% (avoiding the administration of inhibitors or inducers capable of modifying the normal enzymatic activity on a particular substrate) (AD patients may take 6-10 drugs/day); (vii) to enhance efficacy and to reduce toxicity; and (viii) to eliminate unnecessary costs (>30% of pharmaceutical global costs) derived from the consequences of inappropriate drug (or patient) selection and the over medication administered in order to mitigate ADRs.

Ramón Cacabelos, M.D., Ph.D., D.M.Sci.

Professor – Genomic Medicine, Camilo Jose Cela

University, Madrid

President – EuroEspes Biomedical Research Center, Institute of Medical Science and

Genomic Medicine, Corunna, Spain

President – World Association of Genomic Medicine

EuroEspes Biomedical Research Center

www.euroespes.com

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