ISSN 2399-1534 ISSUE 101
THE EARLHAM INSTITUTE
PAUL FARMER, CEO OF MIND
GLOBAL CANCER CONTROL
Employing an innovative computational science and biotechnology approach, the Earlham Institute is bringing biology into the digital age. Director Professor Neil Hall discusses their multidisciplinary approach, current projects, and breakthroughs.
Working within the parliamentary, community and workplace spheres, mental health charity Mind is making waves to combat stigma surrounding mental illness. CEO Paul Farmer shares Mindâ€™s achievements, exciting projects in the pipeline, and long-term strategy.
Cary Adams shares his experience of leadership at an international level as CEO of Union for International Cancer Control. The 1 Research Features organisation employs innovative approaches to tackling the cancer issues the world of today and tomorrow is facing.
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CONTENTS Welcome Being a CEO of an international non-governmental organisation is probably the most challenging thing I've ever done in my life. Cary Adams, CEO of UICC, page 34
60 04 Research News: the latest developments in Health Science research 06 Spotlight on Earlham Intsitute: Leading the data-driven science revolution 10 Healthcare delivery soaring to new heights with interactive simulation
10 48 Planting Seeds of Hope: New drug production method could provide affordable, safe
14 The revolution in cataract surgery
52 Spotlight on One Mind - IMHRO: Opening up discussions on brain health
18 Cutting edge technology gives new vision for old problems
56 Investigating targets for a new class of anti-HIV drugs
22 Spotlight on Mind: Making waves for mental health
60 Promising protein research for neurodegenerative diseases
26 Novel brain-mapping technology could revolutionise pre-clinical drug screening
64 Miracle berries: how blueberries can improve bone health
30 New keys unlock the hidden potential of the melanocortin system
68 Spotlight on UK Biobank: Unlocking the statistics of ill health
34 Spotlight on UICC: Uniting the cancer control community
74 Melanin-regulating ion channels discovery
40 Striking a balance: engineering effective live vector vaccines
78 ADD International: Our work in action
44 Resistance is futile: hybrid drugs become the latest weapon in the biological arms race
80 Break Time: Creating movement for a healthier lifestyle 82 The importance of Social Media
Pharmacology, microbiology, nutrition, neurology, biochemistry, immunologyâ€Ś The complexity and breadth of the field of health science is reflected in the range of researchers we have spoken to for this issue. Whether their work is helping to develop new drugs, contributing to technological advances, unravelling the mysteries of neurodegeneration, or harnessing the power of nutrition, the researchers in this issue all have one thing in common: they are actively contributing to invaluable advances in the arena of health. We also spoke to some of the thought leaders and champions at the forefront of scientific development. Their work is helping to shape global scientific collaboration and increasing awareness around the world Published by: Research Publishing International Publisher: Simon Jones firstname.lastname@example.org Editorial Director: Emma Feloy email@example.com Editorial Assistant: Patrick Bawn firstname.lastname@example.org Junior Editor: Chris Barrell email@example.com Junior Editor: Luna Dewey firstname.lastname@example.org Designer: Christine Burrows email@example.com Head of Marketing: Alastair Cook firstname.lastname@example.org Project Managers: John French, Julian Barrett, Kate Rossiter Contributors: Ella Gilbert, Petra Kiviniemi, Barney Leeke, Kate Porter
Copyright ÂŠ 2016 by RPI Ltd All rights reserved. No part of this publication may be reproduced, distributed, or transmitted in any form or by any means, including photocopying, recording, or other electronic or mechanical methods, without the prior written permission of the publisher.
RESEARCH NEWS It is such an honour. Not all can be successful in science, but it’s important to rise to the challenge. Ohsumi was able to identify genes essential for autophagy, before demonstrating how similar the machinery was between yeast and our own cells.
OHSUMI CELL-EBRATES NOBEL PRIZE WIN FOR AUTOPHAGY RESEARCH A number of infectious, immunological and neurodegenerative diseases are caused by a disruption to this ability to break down and recycle cells and, for a long time, the genes and mechanisms behind the process remained unanswered. That was, however, until Dr Ohsumi’s research came in.
Disruption to this process has been especially linked to Parkinson’s disease, type 2 diabetes and other disorders commonly affecting the elderly. Ohsumi’s findings have therefore provided a foundation for further biomedical research into the mechanisms behind these diseases, in the hope of later identifying potential drug targets. For his groundbreaking discoveries and excellent research, he is highly deserving of this year’s Nobel Prize in Physiology or Medicine, as awarded by The Nobel Assembly at Karolinska Institutet.
THE GENETICS OF YEAST It was not until his series of experiments during the early 1990s that the underlying process behind autophagy became more apparent. Using baker’s yeast, Yoshinori
Speaking of the award Ohsumi said: “All I can say is it’s such an honour. I’d like to tell young people that not all can be successful in science, but it’s important to rise to the challenge.”
A Japanese cell biologist has scooped the Nobel Prize in Physiology or Medicine for his discoveries on the process of cell recycling. Yoshinori Ohsumi, a professor at the Tokyo Institute of Technology, was awarded the prestigious prize for his work studying the mechanisms of autophagy in baker’s yeast. Autopagy translates to mean “self-eating”, following its origin from the Greek words auto (“self”) and phagein ("to eat"). The process is vital to survival, as cells use it as a method to not only destroy invading viruses and bacteria, but to also break down proteins and non-essential components for reuse as energy.
Back in 1992, Dr Ohsumi first proved that autophagy existed in yeast by starving cells and building an accumulation of autophagosomes – vesicles used by cells to transport materials to lysosomes for degradation. Following this major breakthrough, he set about developing a method that identified the key genes involved during this transport process. To do this, he applied a mutation-inducing chemical to the yeast cells, knowing that autophagosome accumulation would be prevented if the genes behind the process were deactivated. By then inducing autophagy himself, he was able to identify the genes used within the cell recycling process, before functionally characterising the proteins encoded by these genes. The results of his extensive research demonstrated that autophagy is controlled by a cascade of proteins and protein complexes, with each regulating a distinct stage of autophagosome initiation and formation.
FANA-tastic New Approach to Combatting HIV Discovered
AUM LifeTech, a biotechnology company with collaborators at the Beckman Research Institute in California and McGill University in Canada, have developed a specific form of FANA RNA-silencing technology that can inhibit HIV replication.
"Such therapeutics involve direct regulation of the genetic factors that are responsible to cause a disease. This approach can also be used to target viruses by manipulating their RNA. In this particular study, we succeeded in effectively targeting HIV RNA and inhibited its replication.” The technology has been shown to efficiently silence and regulate different types of RNAs including mRNA, miRNA, long non-coding RNA and viral RNA – and
that’s not even the best bit. AUM LifeTech has made the technology available to the wider biomedical research community in the hope of advancing genetic research more quickly and more cost effectively. Aishwarya said: "In addition to our therapeutic goals, we would like to help the basic and translational research community all over the world. We hope that our FANA technology will save biomedical scientists a significant amount of time, resources and money to help advance genetic research.” The Philadelphia-based company now plan to use its technology to treat a wide spectrum of genetic diseases, including cancer, neurodegenerative diseases, psoriasis and other viral diseases.
Contraceptive Pill Linked to Depression An association has often been hypothesised but evidence has recently emerged highlighting an increased risk of depression in women who take the contraceptive pill.
of being prescribed an antidepressant than those not on hormonal contraception. More worryingly though, this figure rose to an 80% increased likelihood in girls aged between 15 and 19 on the same pill.
During a recent study, researchers at the University of Copenhagen studied the health records of over a million Danish women aged between 15 and 34. This data was collected from 1995 to 2013 before being broken down and analysed last year.
The alarming study was designed to address the “inadequate association” between hormonal contraception and mood disturbances, according to the researchers involved.
This analysis found that women on the combined pill – which contains artificial versions of the hormones oestrogen and progesterone – had a 23% higher likelihood
However, other researchers in the field were quick to point out that this association was not a cause, stating that many factors other than the pill are involved in depression onset.
LIFE MIGHT NOT BE AS LONG AS WE THINK
US scientists are claiming that humans have reached the peak of their life expectancy. Since the 19th century, life expectancy has been ever increasing largely thanks to advances in vaccines, cures for diseases and safer childbirth. Now, however, researchers at the Albert Einstein College of Medicine suggest that it might not be possible to extend human life beyond the ages of the oldest people on record.
Fresh hope has been offered to HIV patients after US-based scientists recently revealed a promising new method to combatting the disease.
Veenu Aishwarya, founder and Chief Executive Officer of AUM LifeTech said in a statement: “The ability of our FANA antisense technology to be self-delivered without the use of any conjugates or formulations makes it very attractive for the development of nucleic acid therapeutics.
News in Brief
FINALLY, A GOOD EXCUSE TO EAT JUNK FOOD
Scientists at the University of Cambridge have uncovered a gene defect which could explain why certain people crave fatty foods. When offered portions of chicken korma and Eton mess with varying quantities of fat added, participants with defective MC4R genes were found to opt for and prefer the high-fat options available. This ‘fat gene’ typically burns calories and regulates our appetite.
MISSION COMPLETE: ROSETTA’S CRASH LANDING
Back in March 2004, the Rosetta was first launched to perform a detailed study of the 67P/C-G comet. Fast forward almost 11 years to November 2014, and Rosetta's lander, Philae, become the first ever spacecraft to land on a comet nucleus. And now, two years on, it is mission complete. During late September, the Rosetta space probe sent one final transmission before crash landing onto the comet’s surface.
EARLY WEED SMOKING FOUND TO LOWER IQ
Smoking marijuana from a young age causes irregular brain function and a lower IQ, according to researchers. In a recent study published by Lawson Health Research Institute, scientists found that early marijuana users had abnormal brain function in areas related to visuospatial processing, memory and reward processing. They also found the drug had no effect on brain deficits caused by depression.
Leading the data-driven science revolution Director Professor Neil Hall discusses the Earlham Instituteâ€™s multidisciplinary approach, current projects, and breakthroughs, as well as the research instituteâ€™s collaboration with Google to produce the next generation of coders. Employing an innovative computational science and biotechnology approach, the Earlham Institute is bringing biology into the digital age.
t the forefront of modern life science research, the Earlham Institute aims to answer ambitious biological questions, and generate resources that enable academic and industrial investigators to make new discoveries. Established in 2009, the Earlham Institute was founded as a national facility to promote the use of genomics and innovation in the UK. Ever-expanding, the research instituteâ€™s research groups include talented computer scientists, molecular biologists, mathematicians, and geneticists. The Earlham Institute applies computational methods for the collection, analysis and management of large biological datasets - driving progress onwards within the datadriven science revolution.
The DNA foundry is a technical platform to generate synthetic DNA, and enables us to follow-up hypotheses generated from the analysis of large datasets through our in silico analysis and Biological Sciences Research Council (BBSRC), as well as our key collaborators. I ensure that the Earlham Institute remains leading-edge – both in our technology platforms and in the research we deliver. I also have my own research group in microbial genomics. Research Features actively encourages scientific collaboration. How does EI’s multidisciplinary approach improve our understanding of genomics? We believe that transformational changes in research technology are driven by research need. Hence, at the Earlham Institute, we have computer scientists, molecular biologists, mathematicians, and geneticists (along with other disciplines) working side by side. So when one of the research principal investigators thinks “I need to be able to do something we can’t currently do”, our technology platforms can work with the various experts to deliver a solution. This would not work if we were merely concerned with delivering data to external users.
Outlining some of the Earlham Institute’s achievements and long-term strategy, Professor Neil Hall reveals why he thinks there may be a future shift away from viewing biology as the ‘messy, capricious and unpredictable’ sister of ‘clean’ physics. What is involved in your role as the Director of EI? As director, I am involved in setting the strategy for the institute and engaging with our main funder, the Biotechnology
Could you briefly outline EI’s interdisciplinary programme: Digital Biology? Our Digital Biology research programme is dedicated to applying computational methods to the analysis and management of large biological datasets. This can be solving mundane problems, such as how to rapidly and accurately perform quality assessment of large DNA sequencing datasets, to more complex problems like reconstructing biological systems from multiple complex datasets. For example, we are developing methods to take multiple measurements of crops - including images, biochemical data and genetic data – and for processing the collected data, in order to predict which genes need to be selected to increase yields or protect against crop disease. The overarching aim is to take complex data and deliver something that is directly useful to breeders. EI’s recent project, Engineering DNA with synthetic biology, aims to develop novel antibiotics in the future. What progress have
you made so far? Our Engineering Biology research programme is relatively new, with a BBSRC investment of over £3m to set up our ‘DNA foundry’. The foundry is a technical platform to generate synthetic DNA, and enables us to follow-up hypotheses generated from the analysis of large datasets through our in silico analysis. The lab has only recently been completed, with a new Faculty working in this area, including Dr Nicola Patron and Prof Anthony Hall. We have also been collaborating with the Giles Android Group at JIC, who are engineering plants to fix their own nitrogen. There is some way to go before we will be developing novel antibiotics. EI is currently building the basis of a new system for large, energy-efficient DNA sequence searching. How do you think Project GENESYS: Genetic Search System could help future researchers in the health science field? I think the major advantage of the optical processing technology we are testing in this project is that it could make highperformance computing (HPC) available in an affordable and portable system. It is well known to now be faster and cheaper to collect biological data, particularly DNA sequence and images. So, the computational processing of that data is the new bottleneck for biological research, and the expense, running cost and technical expertise is a hurdle that must be overcome for it to be used as a deployable technology in a healthcare setting. In this project, we aim to allow genetic sequence analysis to be performed locally, without the prohibitive running and build costs of HPC systems. What have been EI’s most significant achievements over the last year? There are many candidates for this honour and not all scientific: we have run many successful training events and we have a number of young faculty members who have won prodigious grants which are all institutional achievements. Perhaps one of the most significant achievements was made by Bernardo Clavijo, who worked
We believe that transformational changes in research technology are driven by research need with the Broad Institute, US, to develop a novel computational approach to assemble the wheat genome. This genome is one of the most complex sequenced to date, and to put together the millions of short sequences we generate into a complete genome is a longstanding computational problem. Now this has been achieved, we can start to compare genomes from many different varieties of wheat and also start to understand the genetic basis of important traits, such as disease resistance, drought tolerance, bread-making quality, etc. What is in the pipeline within EI’s long-term strategy? As many of our faculty have been here for less than three years, then a lot will be new. We have a rapidly expanding research field in genomics of fish, both wild and aquaculture species. Fish are growing in importance as a protein source for the growing human population and we need to accelerate genetic improvement. Also, cichlid fish are a model species for understanding natural evolutionary processes like speciation. We also have new faculty working on noncoding RNA, conservation genomics, crop disease, and infield phenotyping. Hence, I expect the next five years to see a real diversification in our work programme. EI is currently collaborating with Google, as a mentoring organisation for the Google Summer Code 2016 programme. How do you feel the partnership will help produce the next generation of coders? The Summer of Code enables young people to contribute to open source software, so that they can do something genuinely useful with their skills. This will hopefully inspire them to enter a career in computing. The Earlham Institute, like many organisations, are helping with mentoring the student volunteers. The fact is that not all young people think of coding as ‘cool’, but Google is widely
Professor Neil Hall, Director of Earlham Institute
recognised as being a cool organisation. Hence, their name alone will help to gain people’s attention. What are you personally most excited about for the future of computational science and biotechnology? There are many practical applications that are coming to fruition currently, like personalised medicine, synthetic biology, and genomic selection in breeding programmes. However, I am actually excited by the possibility that within my lifetime we can derive knowledge directly from large-scale biological data such as genome sequence. We think of physics as being clean, where behaviour follows rules and theory can make accurate predictions. However, biology is thought of as messy, capricious and unpredictable – just too complex. I believe we are getting better at measurement, and importantly, our theory and models are improving so that we might be getting closer to a ‘physics’ world view.
of Liverpool. His research focuses on comparative and evolutionary genomics in pathogens (particularly parasitic protists) to understand the molecular basis of important phenotypes, such as virulence and host specificity. His group also apply genomics to the analysis of microbial communities, in order to understand how they may influence health or respond to changing environments. Neil serves on the Wellcome Trust Biomedical Resources Committee and the BBSRC Exploring New Ways of Working Strategy Panel.
Contact www.earlham.ac.uk @EarlhamInst
• Neil Hall has been working in genomics for over 15 years. He has previously led research groups at the Sanger Institute, The Institute for Genomic Research, and The University
Healthcare delivery soaring to new heights with interactive simulation Dr Robert DiRaddo is the Section Head of Simulation and Digital Health at the National Research Council of Canada. Based in Ottawa, the NRC celebrates its centennial this year. Dr DiRaddo’s team develops mathematically-based and interactive virtual reality technology for a wide range of uses, such as training neurosurgeons, training pilots to fly drones and helping passengers control anxiety.
n its 100th year, Canada’s National Research Council (NRC) is continuing to push the boundaries of technology to deliver new solutions to old problems. Its aims of realism, convenience and affordability are at the centre of the NRC’s drive to advance virtual simulation technology, which has the potential to vastly improve health outcomes for patients. In keeping with this, Dr Robert DiRaddo’s Simulation and Digital Health team has been developing interactive simulators to aid training and improve patient care. Virtual reality (VR) simulators are key to this for several reasons: they can enable longdistance skill sharing and treatment; create an immersive experience to help patients combat conditions such as anxiety, phobia and ADHD; and set benchmarks to monitor
The technology allows training neurosurgeons to practise techniques before they operate on real patients, and helps experts demonstrate or brush up on their skills.
progress, allowing users to improve their skills and develop new ones. RISK-FREE SURGERY TRAINING The NRC’s headline product, developed with simulation technology giant CAE Healthcare, is called NeuroVRTM (previously NeuroTouch). The innovative system provides interactive simulation of neurosurgery procedures. Teaching modules include instrument handling, fundamental skills, endoscopic surgery and microsurgery. The technology allows training neurosurgeons to practise techniques before operating on real patients, and helps experts demonstrate or brush up on their skills. Around 11% of diseases can be treated with surgery, so this technology will clearly play a vital role in healthcare. The simulator is akin to a pilot training simulator, transferring the same principles –
Virtual reality (VR) simulation can be a key part of training and provide critical practice time 11
One practical application of the technology developed at the NRC is to combat in-flight anxiety, which approximately 40% of people reportedly suffer from.
practice of a challenging and vital procedure in a safe, risk-free environment – to neurosurgery. Because teaching hospitals are able to offer less and less actual training time as burdens on health services increase, VR simulation can be a key part of training and provide critical practice time. Nushi Choudhury, a Research Officer for the NRC’s Health Technologies program, highlights the importance of simulation, saying, “when the stakes are high and training in real settings is not feasible, simulation methods have found their niche”. The technology is now being used in 20 teaching hospitals worldwide, some able to communicate over the internet. The simulator employs force feedback technology known as haptics, where the computer gives tactile indicators like in real-life surgery, and relies on the surgeon’s touch to control the simulator. This can reveal what physical cues surgeons are responding
What was the drive behind developing Virtual Reality (VR) technology to improve patient outcomes? VR, or what we refer to as Interactive Simulation, allows user interaction with a mimicked real-life scene, at controlled risk and relatively low cost. It provides a mechanism for objectively quantifying performance measures of skills, for users/patients. If one is able to quantify performance, then one is able to systematically track it to an improved outcome. How versatile is this technology? Do you see it being extended into other fields? There are numerous applications for Interactive Simulation. For example, Interactive Simulation is used in the aerospace sector, mostly to train pilots. It also has applications in the industrial sector for training of skills such as maintenance and operational skills. Simulators to teach drivers also exist. There are also many more examples.
What kind of feedback have you received from students and experts who have used the NeuroVR™ neurosurgery simulation? We certainly have several that indicate its value. One resident indicated her level of comfort was greatly increased prior to her first OR (operating room), largely because of training on NeuroVR™. While there is of course more work to do to increase ‘suspension of disbelief’, NeuroVR™ is currently being used to train residents throughout the world. One such initiative involved the University of Toronto training surgeons in Ghana via Skype, with a NeuroVR™ at each location. How will this technology impact patient procedures? NeuroVR™ targets training. The core technology can be expanded to handle patient-specific rehearsal, i.e. an experienced surgeon practising a complex intervention before going into the OR. Such technology would require work on
facilitating the surgical workflow and assuring compliant technology. How do you develop accurate lifelike models of internal body structures for simulation? We rely on a comprehensive biomechanical tissue testing laboratory for obtaining constitutive mathematical models, relying on Newton’s first principles. We then insert these models into the simulator to increase realism, while assuring a cost-effective simulator. What are your team’s priorities for further developing healthcare simulation technology in the future? Our focus moving forward is to work with clinical and industrial partners: firstly, to deploy constitutive-based simulators in the clinical space; secondly, to expand the use of Interactive Simulation for other applications such as homecare and product development. We are well on our way on both objectives.
VR is a versatile tool that can be applied to many fields and areas to, and help students learn how to conduct procedures. Additionally, it can establish benchmarks to test improvement, and set standards for excellence in neurosurgery. APPLYING EXPERTISE The technologies and expertise at the NRC include physics-based, real-time clinical simulators such as the NeuroVRTM, as well as services for digital health monitoring and custom development for training, for instance using mannequins. The simulated environment can also be used to assess stress levels in other situations outside of surgery. This could be particularly important in outpatient health care, for example allowing home-based care to be conducted remotely, perhaps demonstrating exercises or rehabilitation tasks. It can also be used to assess cognitive performance, for instance in psychotherapy or mental health assessments. This can be useful in treating anxiety or improving fine motor skills. One practical application of the technology developed at the NRC is to combat in-flight anxiety, which approximately 40% of people reportedly suffer from. This can eventually involve immersive VR technology or nonimmersive alternatives such as relaxing music, meditation tutorials and stress-relieving audiovisuals. Similar products have been tested in half of the Spanish airline Iberia’s fleet of Airbus A320s, and installation in the remainder of the fleet is planned to be completed shortly. The technology also extends beyond the flight itself. Simulations of the flying experience include being in the terminal, going through security and actually being on a plane. Anxiety about flying is generally reduced, the more an individual experiences it, but for most people it is not an everyday experience. Simulations can help walk people through the process in advance, helping to reduce the stressfulness of the real life situation. CROSSING CONTINENTS DiRaddo’s team has also used simulations to remotely train other neurosurgeons who are located far away from their base in Canada. Dr Allan Okrainec of the University Health Network (UHN) in Toronto believes that “telesimulation is absolutely the way of the future.” His team conducted the first distance
learning general surgery telesimulation in 2007 with a teaching hospital in Botswana. Since then, more partnerships have been developed with hospitals in developing countries, which can improve the training offered to local neurosurgeons. Teletraining is a good way to cut the costs of training and to share expertise. It is especially useful in developing countries because travelling abroad for training is extremely costly, and beyond the budget of many teaching hospitals. The first use of VR in telesimulation was in partnership with Korle-Bu teaching hospital in Ghana in January 2014. Surgeons at the Toronto Western Hospital UHN delivered training to neurosurgeons in Ghana on how to treat hydrocephalus – an abnormal accumulation of fluid on the brain which has a high incidence in Ghana and predominantly affects children. The procedure can be life-saving but only around a tenth of paediatric patients in Ghana receive it. The live four-week training was the first of its kind worldwide, and was called a “milestone in effectively teaching neurosurgery skills through electronic means” by Marjorie Ratel, President of the Korle-Bu Neuroscience Foundation Canada. WHERE NEXT? VR is a versatile tool that can be applied to many fields and areas. The next steps are to improve interconnectivity between simulators, allowing them to ‘talk’ to each other, and improve the real-life rendering of patient-specific scenarios. This can be achieved by incorporating more highquality data, allowing neurosurgeons to practise scenario-specific procedures before conducting them. The team aims to drive excellence in patient care, and wants to push simulation into common use in medicine. Rolando del Maestro, Director of the Neurosurgical Simulation Research Centre at the Montreal Neurological Institute and Hospital (MNI), and an early supporter of the NRC’s simulation research, predicts, “in the next 5-10 years, I expect every major neurosurgery centre to have simulators”. He adds that “transitioning this dream to an approachable reality will result in a worldwide improvement in the care of surgical patients”.
Detail RESEARCH OBJECTIVES Robert is currently developing a strategy to expand simulation to new fields in healthcare, such as training for other surgical specialties, human factor design of surgical devices, rehabilitation, surgical rehearsal and image enhancement. In this context, his group of 24 employees, in synergy with other colleagues at NRC, are mobilising to offer industry services ranging from custom software development to hardware integration. SOME COLLABORATORS • CAE Healthcare • Mount Sinai (Toronto hospital) • Hopital Foch • Medical University of Vienna • University of Minnesota • University Health Network • McGill University Health Centre (MUHC) • Bayer BIO Robert DiRaddo obtained his PhD in Engineering from McGill University and joined NRC in the early 1990s. Robert developed the SIGBLOW industrial consortium, targeting the delivery of simulation technologies for the automotive, packaging and petrochemical industries. In the mid-2000s, Robert initiated the development of simulation for the medical healthcare sector, in particular for training and device design. Robert holds the position of Section Head and Principal Research Officer at NRC. He also holds adjunct professor positions in the Faculty of Engineering at UBC and at McGill University, as well as an adjunct professor position in the Faculty of Medicine at McGill University. CONTACT National Research Council Canada 75 de Mortagne boulevard Boucherville, QC, Canada, J4B 6Y4 E: Robert.email@example.com T: +1 450 641-5064 W: www.nrc-cnrc.gc.ca/eng/people/ diraddo_robert_8719.html @CNRC_NRC
The revolution in cataract surgery From its inception just a decade ago, the Zepto capsulotomy device has come a long way. CEO John Hendrick tells us the Mynosys story, which shows how a small start-up can shake up the medical field by tackling one of the most challenging and crucial steps in cataract surgery.
ataracts develop when the lens of the eye gradually becomes less transparent, preventing light from entering the eye, and thereby affecting sight. They are often associated with age, and eventually require surgery to treat. According to the NHS, cataracts are the number one cause of impaired vision globally, and most people aged over 65 in the UK have some kind of visual impairment as a result of cataracts. Fittingly, therefore, cataract surgery is the most commonly performed surgery in the USA and EU. Thus, the potential impact of improved technology for cataract surgery is huge, says CEO John Hendrick at Mynosys, who have developed a new ‘Zepto’ device for the job. THE CRUCIAL STEP: CAPSULOTOMY The most important and difficult part of cataract surgery is the capsulotomy. Cataract surgery starts with a small incision in the cornea, the transparent covering over the eye. The surgeon then has to create an opening in the lens capsule, a delicate thin membrane that surrounds the cataractous lens itself. It is through this capsulotomy opening that the surgeon performs the rest of the procedure, including the removal of the clouded lens and the implantation of an intraocular lens (IOL) implant for the best vision after surgery. The capsulotomy is the one step in the operation that is crucial to determining patient outcomes, guaranteeing procedural success, and minimising potential negative side effects. At present, about 85% of capsulotomies are conducted manually, using a procedure called Continuous Curvilinear Capsulorhexis (CCC). However, this is a challenging step, and surgeons vary greatly in their skill – indeed, it is often one of the final lessons of an eye surgeon’s training. IMPROVING EXISTING TECHNOLOGY The need for a technology that can automate and improve the precision of the capsulotomy has been apparent for some time. This has led to the development of femtosecond lasers, which were first demonstrated on human eyes in 2008. Around 15% of capsulotomies now use this method, which is more precise and accurate when making the incision in the lens capsule. This means the surgery is safer and more predictable, so this method can be used in more complex surgeries.
The Zepto capsulotomy tip can collapse to enter the primary corneal incision (A–D), then re-expand to a circle within the anterior chamber (E). Once aligned over the visual axis (F), suction is used to appose the nitinol ring against the capsule. Using a multipulse algorithm, precision-pulse technology is used to cause rapid phase transition of the water molecules underneath the ring, cleaving the capsule membrane and simultaneously creating all 360° of the capsulotomy (G). The tip can then be collapsed and removed (H) along with the excised tissue (I–J).
upfront cost is around $500,000 and there are also ongoing associated maintenance costs. Besides, there is little discernible difference in visual benefits to patients compared with the CCC method, and there have been studies reporting higher rates of certain complications associated with femto. These include ‘postage stamp’ perforations on the edges of capsulotomies, which can cause the capsule to tear. On top of that, it is difficult to operate on patients with corneal opacities or small pupils, who together with those with other comorbidities can make up around a quarter of the patients that a surgeon sees. Lastly, the high cost translates into additional out of pocket expenses of around $1500 to $2000 per eye, making this technology out of reach for the vast majority of cataract surgery patients. THE MYNOSYS STORY The founders of Mynosys, Christopher Keller and David Sretavan, were inspired by the development of femto, but knew that the new technology could still be improved upon. They had been working on developing micro knives for use in glaucoma operations,
but had run up against some brick walls when it came to funding their start-up in a post-recession world. They tried a similar approach with capsulotomies, but soon found that the use of micro knives or any kind of physical cutting on a thin membrane was problematic. That’s where they came up with the idea for Zepto. Chris Keller developed a method called precision pulse capsulotomy (PPC) that uses fast, low-energy pulses of direct current delivered in a hand-held device that replaces capsulotomy forceps directly, meaning it is easily integrated into the surgical procedure. The Zepto device consists of a console, a disposable handpiece and a capsulotomy tip, equipped with a Nitinol ring. Nitinol is an alloy that has shape memory, meaning it can be bent to fit though a tiny (2.2 mm) incision in the cornea, but still springs back to its original size and shape once in place. The ring creates the capsulotomy opening all at once, and does not use tissue cauterisation or burning, therefore minimising the likelihood
Miyake-Apple view footage shows that, compared with CCC, Zepto capsulotomy results in very little zonular movement.
However, ‘femto’ has its downsides, and the most obvious one is the price tag. The
of rips and tears. The tip also includes a suction device, inspired by how squid suckers work to help catch prey, that exerts force to gently pull the membrane against the electrical cutting element without placing strain on other areas. This makes it even more precise and less likely to cause complications. Other benefits of the device include the ability to achieve intraoperative centration – essentially this means centering the capsulotomy opening and placing the IOL over the visual axis (an imaginary line from the fovea, where cones in the eye are most
concentrated and visual acuity is highest, through the pupil) during the procedure. If this cannot be achieved then the patient experiences visual problems because the lens is off kilter. Neither femto nor CCC can currently do this. If you add into this mix the fact that Zepto can shave 12-15 minutes off the cataract procedure in comparison to femto, then you start to see why people are excited about it, and begin to understand where the technology gets its name. Femto is the metric unit meaning 10 -15, while Zepto means 10 -21: so you can think of it as a nerdy way of saying PPC is a million times quicker, smaller and better.
Femto is the metric unit meaning 10-15, while Zepto means 10-21: so you can think of it as a nerdy way of saying PPC is a million times quicker, smaller and better
Capsulotomy is one of the most difficult parts of cataract surgery, what makes Zepto so much better than existing technology? Compared to the manual method of continuous curvilinear capsulorhexis (CCC), it provides fast and consistently excellent capsulotomy results across the entire range of surgical skill. It is very gentle on the zonules so is particularly good for patients with weak zonules, pseudoexfoliation and other complex cataract cases. Zepto also allows for the centration of the capsulotomy anywhere the surgeon desires, including on the patient’s own visual axis to ensure best visual outcome, especially for premium multifocal lenses.
undergo the laser procedure in a different room, then be transported into the operating room for the cataract procedure itself. That is, the laser introduces inefficiency into a procedure where increasing efficiency is the goal. Zepto integrates seamlessly into the existing cataract procedure without requiring surgeons to alter their routine.
Compared to the femtosecond laser, Zepto does not require the hefty $500,000 upfront cost, extra costs per procedure, and it does not require a dedicated space to house a large laser or new personnel to help operate the equipment. The femtolaser adds time to the standard cataract surgery as the patient has to first
It can also help to prevent posterior capsular opacification, which is a common complication of cataract surgery that can cause additional visual disability. The capsulotomy edge produced by Zepto has been demonstrated to be stronger than that produced by CCC or the femtosecond laser. Thus, Zepto may provide a larger margin
How will the device benefit patients? More precise capsulotomy may be beneficial for optimal intraocular lens stability, effective lens position, and to minimize lens tilt. Centration on the patient’s visual axis likely will benefit patients who receive multifocal intraocular lenses that can provide spectaclefree vision post surgery.
A MILLION TIMES BETTER The origin of Zepto sounds like a classic tale of the underdog – two guys working alone, competing with giant companies who were developing femto. They didn’t have the same kind of upfront cash to throw at the project, so they knew they’d have to keep it cheap, simple and effective to succeed. Luckily, they did and the low costs in design have translated into low costs in application. Mynosys CEO John Hendrick says that he’s had a very positive response from surgeons who are keen to get their hands on an easy replacement for forceps that costs around $100 a pop. Hendrick got on board after being convinced by the data on Zepto – he’s certain that it can mount a very serious challenge to both other methods on the market, and the peerreviewed literature suggests the same. In a 2015 paper testing Zepto’s performance, they showed that there were no differences in safety between PPC and CCC, and that the capsulotomy edge was much smoother using Zepto compared with femtosecond technology. When considering the financial angle, time savings and the ease with which
of safety during surgery against capsular complications. There is a great deal of interest in future new generations of IOLs that can use the capsulotomy edge to secure their position post-operatively and thus allow the intended effective lens position to be achieved every time. Zepto facilitates the development of this new IOL technology. Patients with comorbidities, i.e. other concurrent eye diseases, such as pseudoexfoliation, weak zonules, poorly dilating pupils, and glaucoma, may benefit from the use of Zepto as its use is not affected by these conditions and will not worsen these conditions. Patients with these comorbidities comprise on average 25% of cataract surgery patients. Zepto was developed using a pre-clinical model that is regarded to be an excellent simulation of pediatric cataract surgery. Pediatric cataract surgery has a lifelong impact on the patient. It restores vision
Zepto can be adopted, it emerges as a clear front runner. So where next? Zepto has received a CE mark and a 100 patient trial is expected to commence by September. The trial is a singlearm trial that has a four-week follow up. Soon after the trial completion the company plans on filing the 510(k) submission for approval from the FDA. They plan to expand into the market by highlighting the benefits in difficult
cases which make up approximately 25% of the market. There has been excitement not only from physicians and surgeons, but also distributors worldwide, who are keen to see Zepto take off. With this in mind the company will be launching Zepto outside the US in January of 2017. With the recent approval of the small trial in the US it is very possible that the US market could also see a launch about the same time.
Zepto’s evolution from early prototypes to the product being demonstrated today.
in cases of congenital blindness due to lens cataract. The capsulotomy step in pediatric cataract surgery is much more difficult than in adults due to the elastic properties of the capsule. Manual CCC in children has a very high rate of failure and there is no other purpose-designed instrument. Has being part of a start-up given you more opportunities for creativity in developing the technology? It allowed the Company to listen carefully to surgeons, make it easy for others to work with us and react and implement solutions to problems very quickly. What impact do you believe Zepto will have on the capsulotomy technology market? Many surgeons believe Zepto can become the standard of care by automating the most difficult part of the surgery. It can greatly influence how the rest of the surgery will progress and the quality of the outcome for the patient.
What applications do you envisage the technology having in future? Could the principles be applied to other areas of medicine? Our precision pulse capsulotomy technology can be potentially applied to any clinical situation where delicate tissue membranes need to be managed surgically. In fact, Mynosys has obtained preliminary proof of principle that a Zepto-like device can be used to create a capsulotomy in the posterior capsular bag to potentially assist in the prevention of posterior capsular opacification (PCO). PCO is the most common complication of cataract surgery and can lead to a serious deterioration of vision months to years after the original surgery. It is possible that with optimisation for use on the posterior capsular bag, the technology can be used to prevent a complication that currently has a great impact on patient quality of life and is a very large cost burden on the health care system.
Detail RESEARCH OBJECTIVES Our research team brings together diverse technological skills from electrosurgery, shape memory alloys, as well as micro electro-mechanical system design to focus on what many companies have tried to do over the last 30 years. That is to place in the hands of cataract surgeons a disposable capsulotomy device for automated consistent capsulotomies that are dimensionally perfect each and every time. A target market is the adult patient population, where cataract surgery is the most commonly performed surgical procedure in the US and the EU. A second market is for the treatment of lens cataract in infants and children, where capsulotomies in a child’s eye requiring surgery can help restore lifelong vision. CO-FOUNDERS • C hristopher Keller, PhD • D avid Sretavan MD, PhD BIO John N Hendrick has over three decades of executive experience, building both early stage medical device companies as well as large divisions in medical device corporations. Currently, Mr Hendrick is president and CEO of Mynosys Cellular Devices, an ophthalmic company. Previously, he was CEO of NeoVista Inc. a company in the field of Age Related Macular Degeneration. Prior to his accepting the role of CEO with Neovista, he created the Medical Division of Sanmina-SCI. Mr Hendrick has been through a successful IPO of VidaMed which led eventually to the acquisition of the Company by Medtronic Inc. Prior to VidaMed, Mr Hendrick held executive positions in Allergan Medical Optics, Baxter and American Hospital Supply along with several board positions. CONTACT Mynosys, 46710 Fremont Blvd Fremont, CA 94538, USA E: firstname.lastname@example.org T: +1 510-396-1531 W: www.mynosys.com #Mynosys johendrick
Cutting edge technology gives new vision for old problems Professor Roberto Manduchi from the University of California, Santa Cruz, is employing artificial intelligence and augmented reality to develop cutting edge technology designed to assist blind and visually impaired people with access to information.
Could you explain what motivated you to apply your expertise in computer engineering to the development of assistive technology for those with visual impairments? I have always been interested in applications of technology for social good, in particular to support the quality of life of people living with disabilities. Computer vision technology, whose goal is to mimic the functionality of human visual systems, has concrete opportunities to help those who cannot see, or who cannot see well. Since the successful testing of your new mobile OCR system, have you taken its development further? If so, how? We have conducted several experiments with improved mobile OCR functionalities that have shown the promise of this new approach. We are now looking at opportunities to integrate this technology into existing commercial systems. Your research showed that after using the app users learnt to take better images, without feedback from the system. Do you think there is a way that future systems could be designed to make use of this type of learning? This is, in my opinion, one of the most interesting results of our research. It suggests that our system can be used for self-training, meaning that after using it for a while, users may learn the proprioceptive ability that is necessary to take a good picture of a document without sight. The
oss of vision impacts the vast majority of activities in a personâ€™s daily life, rendering the world less accessible. One major impact is not being able to read, which has a huge range of consequences as so much of our information is communicated through text. Roberto Manduchi is a professor of computer engineering at the University of California, Santa Cruz, who is at the forefront of the development of assistive computer vision technology. His work focusses on
idea that a sensorial system could provide important missing feedback to blind users and support learning of tasks that normally require visual input, is very exciting. It could be applied in a number of domains, including mobility, orientation, and tactile information access. What do you feel is currently the most exciting aspect of your research? Although I love developing technology and working in the lab with my students, the most rewarding aspect of this research has certainly been interacting with blind participants, who very patiently test our prototypes and give us critical feedback and advice. This continuous interaction also helps us to focus on the most pressing problems faced by this community, and to appreciate the wide range of abilities that these individuals have, in spite of their blindness. How do you see your research employing augmented reality technology developing over the next 5 years? There is a lot of hype about augmented and virtual reality these days. I believe that wearable camera and augmented reality systems have tremendous opportunities for assistive technology. Realistically, though, these opportunities may only be realised if these systems become mainstream in the computer market, and thus well supported and used by everybody â€“ not just by people with visual impairment.
providing those with visual impairments better tools for accessing text. The outcomes of his research have the potential to be life changing for many people. In the United States over 25 million people are affected by visual impairments, ranging from difficulty seeing despite the aid of glasses to total blindness. 1.3 million are legally blind, 290,000 of those are completely without sight. Access to printed information
is vital if an individual is to live an active and productive life with a high degree of independence. As well as books, magazines and webpages, essential domestic items such as packaging labels on groceries, medicine packets and utility bills, all need to be deciphered. Text also communicates essential information to us on sign posts, the numbers on office doors and menus in restaurants. DIFFICULT TO SEE THE SOLUTION Computer vision is a form of artificial intelligence that aims to mimic human vision so computers can “see” with technology that acts as an “artificial eye”. Manduchi’s recent work has focused on the use of optical character recognition (OCR) technology. OCR is not new, with the first demonstration of a prototype “reading machine”, specifically designed for use by blind people, in 1946. The earliest commercially available OCR machines required imaging of text on a large scanner. While businesses were quick to widely implement OCR for automatic text processing, the large size and immobility of the systems rendered them of limited day-to-day use for visually-impaired users. The introduction of smartphones with high-resolution cameras and the increase of processing power within them, have yielded mobile applications designed to assist a visually-impaired user. However, although computer vision technology has been incorporated into some mobile applications, they are still in their infancy. The first mobile OCR system was released in 2005 with several more released since then. However, current applications have many limitations and difficulties for a blind user. Assistive technology for those with visual impairments must be user-centred to work successfully. The current lack of well-designed, efficient systems is, in part, due to many previous attempts focusing more on the technological aspects of development rather than the prioritisation of the target user’s needs. Manduchi has learnt from the failures of previous decades and is now taking a user-driven research and development approach. Currently available OCR apps rely on the ability of the user to capture a well-framed and resolved image of the printed text. A user can point a phone camera at a text document and have it read out loud in a few seconds. However, the software
needs to first capture an image that it is able to interpret, which is achieved by suitably aiming the camera at the text to be decoded. This can be extremely difficult for a visually impaired user. The camera cannot be so far away that resolution is lost or so close that all of the text will not be in the field of view. In addition, the camera needs to be orientated correctly. Even sighted people can struggle with capturing the right image, so a solution is necessary before a truly effective technology can be created. ADAPTING TECHNOLOGY Professor Manduchi has been working on solving this problem, with the aim of creating a system with a user-friendly interface and rapid processing time that would enable “access to printed matter for blind people anywhere, anytime”. With the aid of his
student, Michael Cutter, he has designed and tested a prototype iOS app that aids the user in taking an OCR-readable image. To achieve this, they tested two different modalities; auto-shot and guidance based. Auto-shot works with the system constantly scanning the camera feed and will take a picture of the target text once conditions for resolution and framing are detected to be satisfactory. This is the method currently in use in most apps. Guidance based systems employ synthetic speech to direct the user to position the camera to take a shot that can be read by the OCR software. Current incorporation of this into existing apps is very limited. Their NIH-funded study, with blind participants testing the different approaches, found that a combination of
Computer vision is a form of artificial intelligence that aims to mimic human vision so computers can 'see' with technology that acts as an 'artificial eye' www.researchfeatures.com
Detail RESEARCH OBJECTIVES Professor Manduchi’s research focuses on assistive technology for persons with visual impairments. Specifically, he is exploring the use of mobile computer vision and wearable sensors for increased spatial awareness and information access. Manduchi is currently collaborating with SKERI, FBK, IBM and CICATA-IPN. He is also a consultant with Aquifi, is on the scientific advisory board of Aira, and served on the BNVT Study Section of NIH.
Requiring all four corners of the document to be visible can be a good strategy in many cases (a), but fails in case the edges are not visible (e.g., white paper on white background (b)) and can be too restrictive (an image could be OCR readable even if not all corners are visible (c).) Screenshots from the iOS Prizmo app. The yellow quadrilateral seen in (a) indicates that the image was captured for OCR processing.
FUNDING • National Institutes of Health (NIH) • Research to Prevent Blindness Foundation • National Science Foundation (NSF)
COLLABORATORS Dr. Michael Cutter, who developed the assisted OCR system during his time as a PhD student in Professor Manduchi’s group.
both systems gave the fastest and easiest assistance to the user. The new algorithm for guidance combined with auto-shot was on average 3 times faster than autoshot alone. Manduchi is now planning on further developing the app based on the results and feedback from visually-impaired users to enable on-the-go OCR of printed documents.
BIO Roberto Manduchi is a Professor of Computer Engineering at the University of California, Santa Cruz, which he joined in 2001. Previously, he held positions at Apple, Inc. and at the NASA Jet Propulsion Laboratory. He holds a “Dottorato di ricerca” electrical engineering degree from the University of Padova, Italy.
Surprisingly, not only did users find the system much more efficient than existing ones, they also found that after using the app they had learnt to take better images without feedback from the system. Manduchi suggests that users increasingly build up a “mental map” that helps them coordinate the camera in relation to the documents they are imaging. SMART READING GLASSES Currently, there is also no system capable of carrying out mobile OCR of text in complex environments. Therefore, the next challenge Professor Manduchi is embarking on is to incorporate the new OCR technology and guidance system into Augmented Reality (AR) glasses for use in domestic surroundings. This system will be designed to magnify text that the person with limited
vision would otherwise be unable to see. Text will be automatically recognised and presented magnified, scrolling across the user’s field of vision. The aim is to enable comfortable reading of not only printed material with complex backgrounds but also text on the screens of appliances and TV subtitles. Importantly, the glasses will also identify text even if the person wouldn’t detect it themselves without magnification. Another project he is working on, funded by Research to Prevent Blindness, is to improve technology that magnifies text on computer screens. Current systems require continual scrolling using the mouse or trackpad. His research aims to combine eye movement recognition software with the built-in camera in computers to magnify text, in real time, in response to where the person fixes their gaze.
CONTACT University of California Santa Cruz Baskin School of Engineering CA 95064 USA E: email@example.com T: +1 831 459-1479 W: www.soe.ucsc.edu/people/manduchi Roberto Manduchi
With researchers now recognising the importance of user-driven research and design, the potential of technology is increasingly being unlocked to develop tools that enable people with visual impairments to have more independent access to information in the world around them.
Making waves for mental health Mind’s Chief Executive Officer, Paul Farmer CBE, talks to Research Features about how he is leading England and Wales’s major mental health charity. Mind ‘won’t stop until everyone experiencing a mental health problem gets both support and respect’.
orking within the parliamentary, community and workplace spheres, mental health charity Mind is making waves to combat stigma surrounding mental illness and achieving significant successes along the way. Thanks to Mind’s helplines and specialist information, millions of people are now receiving advice and support for problems with mental health. Mind has also placed mental health firmly on the political agenda. After many years of campaigning, Mind saw the implementation of the Mental Health (Discrimination) Act 2013 which repealed discriminative legislation that prevented people with mental health problems from serving on a jury, being a director of a company, or serving as an MP. In this feature, Paul Farmer discusses Mind’s achievements, exciting projects in the pipeline, and longterm strategy, as well as the benefits of having a high-profile president.
What does your role involve as CEO of Mind? Quite simply, I’m here to help deliver Mind’s vision that everyone with a mental health problem should receive support and respect. That’s about working with trustees, staff, and volunteers, as well as providing leadership, supervision and direction to managers in order to achieve Mind’s strategy, plans and targets.
From left to right: Frankie Sandford, Mind Ambassador; Stephen Fry, Mind President; Paul Farmer, Mind Chief Executive
A key part of the role is about developing existing relationships and building new ones with a wide variety of supporters of our cause (such as local authorities, professional health bodies and partners) in addition to representing Mind at external events and opportunities. What are your proudest achievements at Mind? Over the last ten years, we’ve seen our cause of mental health grow in importance. Public awareness has improved, which is in part thanks to the Time to Change campaign. Media coverage is now much better, helped by the Mind Media Awards; and political interest is significant - for example within David Cameron’s interview earlier this year, where he pledged ‘a revolution in mental health treatment’. All of these achievements are a result of helping more and more people to be open about their mental health. Mind has had fantastic success in reducing the stigma surrounding mental health. What strategies has Mind found effective for combatting misinformation and prejudices? We’ve seen a huge improvement in public understanding of mental health and attitudes towards people with mental health problems in the last few years, in large part thanks to campaigns like Time to Change - England’s most ambitious programme to end the stigma and discrimination faced by people with mental health problems. The programme is run by the charities Mind and Rethink Mental Illness, and funded by the Department of Health, Comic Relief, and the Big Lottery Fund. Highlighting the high prevalence of mental health problems, and giving people with lived experience a platform to share their experiences, has helped raise awareness and ‘normalise’ mental health problems. Growth in awareness is also down to increased access to information, both physical and digital. All information produced by Mind is certified by the Information Standard,
and bears its quality mark, indicating that it is reliable and trustworthy. Our network of around 140 local Minds across England and Wales are vital - not just in terms of providing support to local people affected by mental health problems, but also for increasing awareness and disseminating information. Stephen Fry took over the role of Mind’s president in 2011 from Lord Melvyn Bragg. How have you found Stephen’s contribution helpful for raising awareness of mental health issues? Stephen’s 2006 documentary The Secret Life of the Manic Depressive detailed his own and others’ experiences of bipolar disorder. His film helped raise awareness of an often misunderstood condition, and challenged the stigma surrounding mental health problems. Stephen was subsequently named the 2007 Mind Champion of the Year in a public vote. Having a high-profile president and figurehead allows us to further promote our causes to a wider audience than we would otherwise reach. Stephen has been,
We’ve seen a huge improvement in public understanding of mental health and attitudes towards people with mental health problems in the last few years
and rescue workers; so we need greater investment in promoting wellbeing to enable them to perform at their best – and continue to carry out these difficult and life-saving roles we often take for granted. Can you tell us about your Workplace Wellbeing Index? Mind has a dedicated Workplace Wellbeing team that advises employers on how they can create mentally healthy workplaces. This involves tackling the causes of work-related stress, and promoting wellbeing for all staff; so we have just launched our Workplace Wellbeing Index – a benchmark of best policy and practice when it comes to promoting good mental health among employees. The first set of results will be out in March next year. Find out more at: www.mind.org.uk/ index We love the sound of your ecotherapy program. Could you briefly tell us more about this, and any other innovative approaches you are developing? Ecotherapy covers a wide range of treatment programmes which aim to improve mental and physical wellbeing through doing outdoor activities in nature.
and continues to be, a tireless campaigner, supporter, and advocate for everyone experiencing mental health problems. In 2015, Mind funded research that found 9 out of 10 emergency services personnel are affected by stress. Do you feel that this issue is now being addressed? Since March 2015, Mind has been delivering a ‘Blue Light Programme’ to provide mental health support to emergency services staff and volunteers. Since then, we’ve seen 300,000 information resources disseminated; over 5,000 managers participate in line manager training; over 440 emergency service staff register to be ‘Blue Light Champions’; and 56 Blue Light employers and 9 national associations sign the Blue Light Time to Change pledge – a commitment to raising awareness of mental health, tackling stigma, and helping people talk more openly about their mental health. Stress, anxiety and depression remain very high across fire, police, ambulance, and search
Active Monitoring is one of our latest products. Developed by a service user at Tameside, Oldham and Glossop Mind, this early intervention programme helps prevent mild to moderate mental health problems like depression and anxiety escalating while people are waiting for treatment. Delivered over five sessions in eight weeks, it is a similar approach to Cognitive Behavioural Therapy (CBT). It has had great success in terms of reducing anxiety and depression, and we hope to roll it out more widely across England and Wales. ‘Get Set to Go’ is Mind’s programme to support 75,000 people with mental health problems to take up sport, with support from Sport England and the National Lottery. We know physical activity is good for wellbeing, so eight local Minds are helping support people with mental health problems to overcome their barriers to exercising and become more active.
How did it feel to be awarded a CBE by the Queen this year for your outstanding services to mental health? It was a real honour for mental health to be recognised and Mind’s work to be credited in this special way. It’s also a chance to thank members of my family, who have to put up with a lot! Mind’s 2016–21 strategy is called ‘Building on change’. Can you briefly explain what this will involve? Since launching our previous strategy in 2012, we’ve seen some significant changes in mental health. In the past four years, public attitudes have improved, support has grown and mental health is higher on the political agenda than ever before. But we know there is much more to do. Our new strategy will focus on five areas – services and support, empowering choice, social participation, staying well and removing inequality. Find out more at http://www.mind.org.uk/about-us/ our-strategy/. What do you personally hope future research should focus on to help individuals who experience mental illness? The 5 Year Forward View for Mental Health, a report from the independent Mental Health Taskforce to the NHS in England, called for a research strategy for the next 10 years, with increased investment needed. We need additional effort in all areas: how to prevent mental health problems; more effective treatments; more social and user-led research. • Paul Farmer has been Chief Executive of Mind since May 2006. He is Chair of the Association of Chief Executives of Voluntary Organisations (ACEVO), the leading voice of the UK’s charity and social enterprise sector. Paul is also Chair of the NHS England Mental Health Taskforce, helping to create the Five Year Forward View for Mental Health for the NHS in England.
Contact www.mind.org.uk/ @paulfarmermind
Mind has also just launched a campaign urging anyone who is worried about their mental health to speak to their GP. We know it can be difficult to speak to GPs about your feelings, so we’ve put together a guide called ‘Find the Words’, which offers advice on how to take that first step and have the conversation.
Novel Drug Development
Novel brain-mapping technology could revolutionise pre-clinical drug screening Dr Pavel Osten, MD, PhD, is co-founder of Certerra Inc., a company whose PharmacomapTM technology uses a novel method called iDISCO to generate whole-brain maps of drug activation. With this approach, Certerra provides its customers, small and large pharmaceutical companies, with a comprehensive screening tool to help identify which new potential drugs are the best candidates for clinical trials, greatly improving on existing preclinical methods and accelerating the process of drug development.
What motivated you to target CNS drug assessment? There have been very few new psychiatric medications brought to the market in recent decades; most of the medications that we have, have come from serendipitous discoveries made a long time ago, in the fifties and sixties of the last century. In my view, this lack of progress is largely due to a lack of preclinical methods that could be used to quantitatively and rapidly assay drug-evoked activation at the level of the whole animal brain. Having worked on questions of basic neuroscience research in my earlier carrier, I was motivated to try to improve existing technologies and set up the first quantitative and high-throughput method for preclinical drug screening. What came first, your whole-brain screening methods or the desire to hone the process of pre-clinical drug testing? The desire came first. I was thinking about how to image the whole brain of a mouse or a rat for screening drug-evoked responses. At that time, two-photon microscopy, that we used to establish our first pipeline based on STP tomography, was the most advanced high-resolution imaging method. Since then, a method called light-sheet fluorescence microscopy (LSFM), has become a faster and cheaper alternative and we have moved quickly to adapt this method, together with the wholebrain immunostaining protocol iDISCO, into our drug-screening pipeline. How similar are neurological disorders in mice and humans? They are certainly not similar. We also don’t think that there really can be a good animal model of psychiatric medications and the use of such ‘models’ (either behavioural or pharmacological) in the past has not led to any new drug developments. What we believe is that the rodent brain has a sufficient computational capacity (it’s a big enough computer) to ‘distinguish’ responses evoked by different drugs, both between classes (for example, antidepressants from antipsychotics) and, within classes, between different generations of antipsychotics (for example, SSRI’s from MAOI’s from TCA’s).
We have, in fact, shown that this is true by screening all 61 medications commonly used in psychiatry today, and generating a specific PharmacomapTM for each drug. Having done this, we can now use this library to test new compounds and identify: 1) Whether they have any activity in the brain at all (for example, many drugs do not cross the blood brain barrier and thus fail in vivo even though they had the desired activity in in vitro assays). 2) Whether this activity resembles the activity of the known drugs. 3) W hether the activity may have possible side-effects. The side-effect question we can address based on structure–function homologies between the rodent and the human brain, since most side-effects involve brain regions that regulate autonomic and endocrine functions and those are well shared between rodents and humans. You say you’ve had a positive response from the pharmaceutical industry – has anyone been able to suggest improvements? With our first pipeline based on STP tomography, our throughput was much slower and therefore the cost per test was quite high (about $25,000 per one compound). We were also limited to only one gene – c-fos – that we could use as a marker of neuronal activity. Thus the main suggestions/requests from our customers have been for a lower price, larger volume and a broader assay. We are now able to offer all those improvements. Certerra Inc. has ambitions to expand its horizons beyond CNS drugs – how widely do you think this method could be applied? We are focused currently on CNS and we want to broaden our service to be able to test drugs, not only for psychiatric disorders, but also for neurodegenerative disorders, including Alzheimer’s and Parkinson’s. In the non-CNS market, we envision that our assay could help with assessing whether medications targeting peripheral organs may have unwanted CNSbased side-effects. We may think about developing specific assays for other disorders in the future, including cancer, but that is not our immediate focus.
Novel Drug Development
erterra Inc. was founded in 2011 by Dr Pavel Osten, MD, PhD, Associate Professor of Neuroscience at Cold Spring Harbor Laboratory (CSHL) and Sebastian Seung, PhD, Professor of Neuroscience at Princeton. It is a biotechnology company that has developed a novel type of assessment for central nervous system (CNS) drugs. This approach uses high-resolution brain imaging and sophisticated statistical analysis to map the extent of brain activation induced by potential new drugs in animals. The resulting whole-brain cellular map of pharmacological activation is termed a ‘PharmacomapTM’. This method is the first among its competitors to successfully measure the effects of a drug at single neurone resolution across the whole brain, representing a major advance in the preclinical CNS drug discovery market. WHY IS THE TECHNOLOGY SO NOVEL AND NECESSARY? At present, almost 90% of CNS drug trials fail at the clinical testing stage, a key cause for the diminishing returns in the pharmaceutical industry. There is, therefore, a great need to be able to assess the merit of potential pharmaceuticals at the pre-clinical stage. Certerra Inc.’s method greatly assists with this goal. It is particularly important to test the efficacy of new molecular entities (potential drugs) in vivo, i.e. in live animals. This is because CNS drugs work on the most complex part of the body, the brain. Testing them in vitro in a petri dish simply cannot replicate the complexity of the living brain. Clinical trials cost vast sums of money, can be extremely risky and take a lot of time. Certerra Inc.’s technology presents a way of spotting drugs that are more likely to fail, thus avoiding the associated costs in clinical trials. Pharmaceutical companies benefit because they can then invest more time and resources into the research and development of drugs with a higher likelihood of success. This is very important because it will help accelerate the process of making treatments available for neuropsychiatric illnesses, greatly benefitting patients. CURRENT INDUSTRY UNDERSTANDING There has been considerable work to improve pre-clinical drug screening, but most methods that aim to improve the predictability of drug trials focus on in vitro screening. These assays are used to optimise
Three-dimensional overview of the brain activation pattern – the PharmacomapTM – evoked by the antipsychotic drug Risperidone, showing robust activation (red color) in several brain areas, including the caudoputamen and cortex.
Working with Otsuka Pharmaceuticals, Certerra Inc. provided a highly valuable preclinical assessment of a new treatment that is now available for schizophrenia and depression the drug design process to target specific molecules or properties. However, these methods fail to illuminate how the drug works in complex organ systems. Other assays quantify changes in rodent behaviour after treatment with a drug. However, animal behaviour is a simplistic and incomplete model of human behaviour, making it difficult to extrapolate animal (rodent) behaviour up to the level of complexity required to determine the potential drug effects in humans. Multi-modal imaging alternatives, such as PET and MRI, can be performed. However, these operate at a low resolution (unable to resolve brain activity at the cellular level), and must be performed on anaesthetised animals. These factors therefore limit the interpretation of the effects of the substance on the brain. Certerra Inc.’s PharmacomapTM technology, in contrast, achieves analysis of drug-evoked, whole-brain activation in behaving animals, at single cell resolution and high throughput.
Certerra Inc. has moved to a larger facility at the Broad Hollow Bioscience Park (NY) this year and is gearing up to be able to screen thousands of novel compounds per year. This means that Certerra Inc.’s research could greatly improve the predictability of drug effects before clinical testing. THE SCIENCE BEHIND IT The central hypothesis that underlies Certerra Inc.’s approach is that ‘the effects a drug has on the brain are largely determined by which neurones it activates’. This is rooted in the essential neuroscientific understanding of the way neurones form complex networks and how their activity drives mental activity. Dr Osten and Certerra Inc. believe that this is the key reason that so many CNS drugs fail at the clinical testing stage – the absence of a method to determine brain-wide drug activation of specific neurones at sufficiently high resolution to make it useful. HOW IT WORKS The core of Certerra Inc.’s approach is their use of two recently-developed technologies:
Detail RESEARCH OBJECTIVES Dr Pavel Osten and the team at Certerra Inc. provide, through their unique PharmacomapTM technology, an opportunity to assess the likely success of CNS drugs at the preclinical stage. COLLABORATORS Sebastian Seung, Princeton
iDISCO whole-brain immunostaining in combination with light sheet fluorescence microscopy, which can provide automated imaging of whole organs at cellular resolution. Specifically, the iDISCO maps the drugevoked induction of molecular markers for neural activation called immediate early genes, such as c-fos or Arc. This can be used to create unbiased, whole-brain maps of neural activity when stimulated by particular drugs - PharmacomapsTM. The whole-brain activity map is then statistically analysed to identify the regions where activity was significantly altered by the drug. Correlations identified between drug effects and structural features in the brain maps can be used to target candidate drugs for further development. The aim of the (successfully completed) first phase of development at Certerra Inc. was to be able to discern all common psychiatric medications used in the clinics, based on their PharmacomapsTM, essentially generating a fingerprint for each medication. Having demonstrated that the technology can assesses the extent of drug-evoked activation in the mouse brain, the company now aims to use this data to improve the ability of the technology to predict the efficacy of substances in the human brain. To do this, Certerra Inc. have created the first animal-to-human (A2H) database of PharmacomapsTM, linking pharmacomaps of
61 psychiatric medications to their clinical effects and side effects. This can be statistically analysed to determine the extent to which the database can be used to predict human outcomes. Certerra Inc.’s work over the last three years with Otsuka Pharmaceuticals represents a successful application of the PharmacomapTM approach to preclinical drug screening. In this project, Certerra Inc. was able to provide a highly valuable preclinical assessment of a novel compound, called brexpiprazole that was successfully introduced as a new treatment for schizophrenia and depression in autumn, 2015. NEXT STEPS The positive reception from industry veterans suggests that Osten and Seung’s technology could go far. The third phase of development will involve Certerra Inc. contracting their services internationally and industry-wide. In addition to psychiatric disorders, Certerra Inc.’s technology can also be used to study neurodegenerative disorders, such as Alzheimer’s and Parkinson’s. Certerra Inc. aims for their technology to become an indispensable part of the drug development pathway, honing the process and speeding up the delivery of new drugs. Given the speed with which the company has grown already, their method may very well become ubiquitous.
BIO Dr Pavel Osten obtained an MD from Charles University in Prague and a PhD from State University of New York, Brooklyn. He trained with Dr Ed Ziff at New York University and Dr Peter Seeburg at the Max Planck Institute in Heidelberg. At Cold Spring Harbor Laboratory (CSHL), Dr Osten has led a team of scientists in establishing STP tomography as a state-ofthe-art method for standardised, high-throughput and unbiased screening of neuronal activation in the whole mouse brain at cellular resolution. He and a colleague, Sebastian Seung (Princeton), started Certerra Inc. in 2011, in order to commercialise this STP technology for the screening of drugs targeting the central nervous system. Dr Osten has authored and coauthored over 50 papers, reviews, and book chapters, and was the recipient of the McKnight Technological Innovations Award in 2009. CONTACT Pavel Osten, MD, PhD Founder, Director Certerra Inc. Associate Professor Cold Spring Harbor Laboratory 1 Bungtown Rd NY 11724 USA E: firstname.lastname@example.org T: +1 516 367 6990 W: https://www.cshl.edu/Faculty/PavelOsten.html http://www.certerra.us/
New keys unlock the hidden potential of the melanocortin system A system of receptors, the structure of which has been conserved through millennia of evolution, are being targeted by Prof Victor J Hruby and his team at the University of Arizona, opening the door to new treatments for a panoply of diseases.
Novel Drug Development
What has been the most significant advance in peptide synthesis during your career? â€˘ O ptimised solid phase peptide synthesis including the use of microwave methods for some aspects â€˘ T he ability to form many different kinds of constrained and cyclic and macrocyclic peptide structures with designed conformations and topographical structures â€˘ Asymmetric synthesis in chiral chi space What is the greatest challenge in getting novel compounds in to clinical trials? People! Money! Clinical trials are expensive, and most people in most drug companies fear novel compounds, and do not want to think about or do something novel. Who has the potential to benefit most from your research? Ultimately sick people! Currently, medical doctors, biologists, and medicinal chemists
who wish to explore new modalities for the treatment of disease. What is there still to discover about GPCRs? We know very little about GPCRs, so there is still much to discover! Especially how their structures change in response to ligands that interact with them, and how these structural changes lead to changes in biological activities. Also, how downstream signalling is differentially affected by the different ligand-receptor structures. What other applications or treatments is this technique likely to open up? We now have highly receptor-selective orthosteric and allosteric agonists and antagonists for the MCiR, MC3R, NC4R and MC5R. This will provide new tools to discover new biology associated with the MCRs. This, in turn, can lead to new leads to new approaches for the treatment of many of our most common degenerative diseases including mental illness.
This work can lead to new approaches for the treatment of many of our most common degenerative diseases, including mental illness
Novel Drug Development
he melanocortin system of receptors is a group of five G-protein coupled receptors (GPCRs), a common receptor type which spans the cell membrane to sense molecules outside the cell. When a specific molecule is bound on the extracellular portion, the protein undergoes a conformational (shape) change which releases molecules inside the cell to stimulate intracellular signalling pathways. These receptors are generally very specific for their activating molecules, known as ligands, and this is particularly true for the melanocortin family. Melanotropins bind to a particular site on the protein, created by a unique sequence of amino acids; each of the naturally occurring receptor sub-types is the result of evolutionary selection of minor variations in these binding sites. The melanocortin family of receptors has sites which include highly conserved sequences (the same layout of amino acids in each of the receptors). This makes it more difficult to find or create ligands which will be specific for just one receptor sub-type. THE MASTER LOCKSMITH With nearly forty years of experience in the field, Prof Hruby has dedicated his lifeâ€™s work to developing novel ligands for GPCRs, and designing and synthesising biologically active peptides and their mimetics (molecules that mimic the behaviour of these proteins). Through analysis of the conformation, dynamics and biological activity of these transmitters, particularly those that relate to human behaviour, he has uncovered potential treatments or drug targets for the control of pain, obesity and sexual behaviour among others. There are significant challenges to designing and synthesising peptides with very specific biological activity. Modern computer modelling techniques and computational chemistry have made it possible to test the theory of novel molecular constructions and their interactions. However, there then follows complex and painstaking work to realise the compound and test its structural biology. CRACKING THE SAFE Prof Hrubyâ€™s team had to make use of previously proven methods of protein synthesis to create the peptides they had designed. They then used High Pressure Liquid Chromatography to purify them. A second chromatography method (Ion Exchange Chromatography) or gel filtration
is then utilised for the final purification and analysis steps. All this before their biological action can even begin to be investigated; competition binding assays (seeing how it competes with a known ligand labelled with a radioactive isotope) and functional assays in cultured cells which express the receptor on their surface, are employed for this purpose. This work, though laborious and complex, has the potential to influence many treatments being used to moderate human health and behaviour. Often, people associate the prefix melano- with pigmentation disorders such as the skin cancer melanoma and albinism’s opposite number, melanism. Endogenous peptide hormones, made within the body to act on the melanocortin system, do indeed regulate pigmentation processes, so novel ligands have the potential to be utilised to adjust these. Some of these hormones also act at other receptors, such as those associated with pain, so mimetics of these have the potential to relieve that pain as novel analgesics without the problems of addiction associated with substances such as opiates. THE BRAIN IS KEY The field has now opened up even further with the relatively recent discovery that other aspects of human behaviour disorders, such as the regulation of appetite, have their roots in this system. In recent studies of sub-types three and four of the melanocortin receptor, removal of these receptors in mice had a complex effect on obesity and related diseases, such as diabetes, which is not completely understood. Other studies have shown that mouse models, with a genetic variation which makes them prone to obesity, endogenously express a protein which activates these receptors (an agonist). Conversely, chemicals which compete with the agonist for the binding site but without generating a response (antagonists) inhibit this overeating activity. Novel compounds, with high specificity for a particular receptor sub-type and antagonist activity, are
therefore of great interest in the treatment of certain eating disorders.
Prof Hruby’s team have pushed ever deeper into the realms of human behaviour disorders with their research into the role of melanocortin receptors in erectile dysfunction. Following successful research in mice, clinical trials of melanotropic peptides have shown significant positive effects on both erectile function and the more complex issue of sexual appetite.
RESEARCH OBJECTIVES Professor Hruby’s research focuses on the melanocortin 1, 2, 3, 4 and 5 receptors and designed ligands that will act on these receptors. The receptors are involved in many diseases including pigmentary disorders, melanoma cancer, stress, immune response, sexual dysfunction and behaviour, feeding disorders including obesity, neurodegeneration and many others. The ligands therefore have an extremely wide field of potential applications.
The regulation of appetite and sexual activity is clearly linked to this receptor subpopulation of types three and four, which is predominantly located in the brain and spinal cord. This brings particular challenges around the design of peptides and mimetics which are able to cross the notorious blood–brain barrier and reach the desired target. As the different sub-types clearly interact with each other in mediating physiological responses, it is necessary to develop compounds which are able to cross this barrier and act at one type, as well as those which are unable to and will instead act at another. Highly specific agonists and antagonists with these properties have been developed by the team and are in the process of being rigorously tested for efficacy. A LOCK ON EVERY DOOR With the melanocortin receptors also associated with the regulation of cardiovascular function, through blood pressure and heart rate, and kidney function in terms of salt secretion and high blood pressure related to salt sensitivity, there are clearly many applications for melanotropins yet to be uncovered. Due to his extensive experience of creating and evaluating novel peptides and their mimetics, Prof Hruby and his team are perfectly placed to continue pushing at these previously locked doors. The keys they are creating promise to unlock new treatments, ones which will treat the diseases threatening to become ever more prevalent in the ageing populations of developed economies.
Their work promises to unlock new treatments, ones which will treat the diseases threatening to become ever more prevalent in the ageing populations of developed economies www.researchfeatures.com
FUNDING National Institutes of Health (NIH) COLLABORATORS • Professor Mac E Hadley (deceased) • Professor Robert Dorr • Professor Roger D Cone • Professor Norm Levine • Professor Hunter Wessells • Research Professor Minying Cai • Dr Tomi Sawyer And many others worldwide BIO Dr Victor J Hruby received his PhD from Cornell University in 1965 and did his postdoctoral research with Nobel Laureate Vincent du Vigneaud. He has been a professor at the University of Arizona in the Department of Chemistry and Biochemistry since 1968. His major research interests are in peptide hormones and neurotransmitters and their receptors in relation to human behaviour and degenerative diseases. He has over 1200 publications. CONTACT Prof Victor J Hruby Regents Professor Emeritus Department of Chemistry and Biochemistry 1306 East University Boulevard PO Box 210041 University of Arizona, Tucson, AZ 85721 USA E: email@example.com T: +1 520 621-6332 W: http://uacc.arizona.edu/profile/ victor-hruby
UICC Uniting the cancer control community Research Features speaks to Cary Adams, CEO of Union for International Cancer Control (UICC), about their innovative approaches to tackling the cancer issues the world of today and tomorrow is facing. Cary shares his experience of leadership at an international level and the rewards and challenges it can bring.
orking alongside key collaborators, such as the World Health Organization and other UN agencies, the nongovernmental organisation is dedicated to taking the lead in uniting the cancer community to reduce the global cancer burden, promote greater equity, and integrate cancer control into the world health and development agenda. UICCâ€™s determined efforts are reaping rich rewards â€“ clearly evident in the fruition of significant successes. The NGO is giving cancer a run for its money â€“ and not just economically.
How would you define your role and responsibilities as the CEO of UICC? Within the organisation, I play a significant role that involves working on behalf of our membership around the world, as well as our board, to make sure that UICC delivers exactly what is set out in our long-term business plan. As the CEO, my job is to make sure that we do have the impact globally that we plan to have. Being a CEO of an international nongovernmental organisation is probably the most challenging thing I've ever done in my life. Your whole role is to influence individuals and organisations from around the world who really don't have to listen to you. To get the World Health Organization and the United Nations to listen to the people who have a passion about improving cancer control around the world means that we have to constantly work with individuals and organisations that really could be doing something else. Therefore, to deliver our agenda, the agenda of many, many people around the world who care about cancer, we have to work in a very open space where advocacy and influencing are absolutely critical to the role of the CEO. So, it's a very challenging job. I really love doing it – people that I know who do equivalent jobs for other international organisations thoroughly enjoy their roles as well – but it is extremely challenging and tiring at the same time and I think I've aged a bit in the last few years. What drove you to change career from banking in 2010 to leading UICC? Well, I think it was a sequence of things over many years but I guess we all get to a point in our life when we recognise our career in one domain is probably coming to an end, and certainly mine was. I thoroughly enjoyed working in the banking industry for many years but it was becoming obvious to me that it was time to move on. I really didn't know too much about what I wanted to do. I then worked with a charity in the UK for a couple of years and I really respected what they were doing, so I knew after that I wanted to do something which had social impact. And then, just by real good fortune, a head hunter who had been appointed by UICC to find a CEO contacted me, and sent me the job description.
It really resonated with me immediately, not least because, like most people, my life has been touched by cancer, by losing friends and family. But importantly, whilst the nature of the role just seemed to be so demanding and challenging, the end point of doing a good job would be that you would influence the lives of future generations – that was a very compelling attraction to apply for the role. And of course, I was then extremely lucky to secure it seven years ago. Last year you were awarded ‘CEO of the year’ at the International and European Associations conference. How did it feel to be given recognition for your work and UICC’s successes? It was extremely humbling. The International and European Associations Conference is such a well-respected event, and the organisation behind it also has a great reputation itself. It was first of all incredibly humbling that, one, my name was even considered and secondly to win it made a very enjoyable evening, to say the least, because many of my team were there when the announcement was made. But I would say that, like most awards, the award for me as an individual is completely down to the hard work of so many other people. It's very difficult as a CEO to achieve anything without great people around you, without the support of a board, without the involvement of key individuals around the world. The judgement of any CEO's performance, at the end of the day, is the impact that their organisation has and the method through which they achieve that impact. So, it was humbling at a personal level, but it was also a very proud moment. It was, for me, a tick to say that the UICC had achieved so much in the previous four years. And just to reinforce that point, this year we also won an award for conference development for our World Cancer Congress. I think this again confirms that what we have in UICC is a team that's passionate about working with its membership around the world. So we're very proud of the fact that
all of our hard work has been recognised by these organisations with such good reputations. Thinking back over the last 12 months, what do you think has been UICC’s most significant achievement? Now that's an interesting question because we operate in so many different domains. But I will pull out one or two things that I am personally proud of. They're probably not the things that necessarily grab the attention of the media, but nonetheless they are so important in terms of taking things forward for the global cancer control community. First would be the extension of the World Health Organization's (WHO) Model List of Essential Medicines. To give you some background information, all countries around the world look towards the WHO as the leading guide on how they should be addressing health within their country. And the Essential Medicines List is essentially what it says – it's a list of medicines that should be available in every country to help address all the diseases which they face. However, the Essential Medicines List has not been reviewed for about ten years for the issue of cancer. Collaborating with nearly 100 experts from around the world, UICC worked diligently with WHO staff to put forward a recommendation to increase the number of medicines on that list from 30 to 46. After such a significant increase in such a short period of time, I must admit that there was a certain amount of celebration last year when we were able to get this agreed by the WHO and to publicise the achievement around the world. Our success will impact the lives of people around the world in the next 10, 20, 30 years, as those medicines could come available to other countries who can use them to resolve childhood cancers, breast cancers, and other cancers. So I would say that was probably the most rewarding win in the last twelve months. But, of course, that's very much in the background as one of our successes. Meanwhile there have been lots of other
Being a CEO of an international non-governmental organisation is probably the most challenging thing I've ever done in my life www.researchfeatures.com
more public wins, such as when the United Nations (UN) announced in New York that cancer and other non-communicable diseases, or NCDs as they're called, are in the UN’s sustainable development goals. We worked diligently with about 40-50 organisations from around the world, if not more, to ensure that cancer and other NCDs would actually feature in the United Nation’s Sustainable Development Goals as they previously haven’t. I believe that augurs well for the future. Every country around the world will now need to position cancer, and the other NCDs, in the same place as they would be addressing communicable diseases like HIV/Aids and malaria. So again, a significant international agreement, which will filter through to national policies and national actions over the next 10 to 15 or 20 years. Could you describe UICC’s long-term strategy? Our long-term strategy is actually defined by our board, and it's reviewed every four years. A couple of years ago the
board spent two and a half days discussing what UICC should be doing over the next 10, 15, 20 years. They came up with some conclusions which I think are quite compelling and actually filter straight down to what we do on a day-to-day basis. The first one they decided was that UICC's role should be to maximise resources for reach and impact. For example, how can we play a role to get more resources into the cancer community, and then disseminate that to the people who need it in the most impactful way? And of course, that's one of the reasons that we're focusing on capacity building globally. But our ambition is that we should use all new technologies, social media, etc. to get information out to people who need it in the most impactful way.
After all our global wins, such as achieving targets for cancer and the NCDs to be in the Sustainable Development Goals, the second area of long-term focus is about ensuring that governments follow through on those commitments and those promises and establishing in the mind-set of all of our members around the world that they have to play a role to support governments to fulfil those obligations. They may be obligations, for example, to reduce tobacco use by 30% by 2025. Well the question is, how can the cancer community work with governments to make sure that they put in place the laws required, the tax rises required, to achieve that objective? Because those objectives weren't just made up. They were considered long
Every country around the world will now need to position cancer, and the other NCDs, in the same place as they would be addressing communicable diseases like HIV/Aids and malaria www.researchfeatures.com
The UICC Team celebrated 1,000 member organisations in the Parc des Eaux-Vives in Geneva, Switzerland.
and hard by the World Health Organization, as being a combination of targets, which at the end of the day will benefit society when it comes to cancer and NCDs. So one of our key ambitions is to play a role to hold others to account who make promises, not to agitate them but to make sure that we support, guide and help them in those ambitions. And then the third area that we are looking at we call 'Leading and Inspiring a Movement'. That's really about growing the UICC membership base from 1,000 organisations at the moment, and doubling it over the next 5–10 years. But it’s also about engaging individuals, identifying young leaders of the future, and possibly some of the researchers that we were talking about earlier, and giving them the opportunity to become the global leaders of the future. Well, where are those young people today? If I look at my board and my president now, I've got Mary Gospodarowicz from Canada, I've got Tezer Kutluk from Turkey, and I've got Sanchia Aranda from Australia. All incredibly successful, ambitious, energetic individuals who play an absolutely critical role in the way the world thinks about health in the future. We're the ones from twenty years ago – how did we get through it? There are, amongst many others, some key questions: How do we identify young talent
now, so that they are given a good chance to play a global role at some point in the future? How can we help all of our members to hopefully do a better job at working with us on World Cancer Day, attending the Congress, the Leader's Summit? The three areas of what we want to achieve long-term, which translate into the work we do on a day-to-day basis, are threefold: firstly, how do we maximise resources for
reach and impact; secondly, how do we take responsibility and hold people to account who have made commitments to help the cancer community in the future by helping, guiding, and supporting them; and finally, what should we do to lead and inspire a global movement over time, so that more people feel comfortable talking about cancer, because they understand that there are things that have been done to actually address it.
Detail BIO Born in London, Cary Adams has a BSc Honours degree in Economics, Computing and Statistics from the University of Bath, United Kingdom and a Masters degree (with Distinction) in Business Administration. He is a Harvard Business School Alumni having attended the School’s Executive General Management programme in 2003. In 2009, Cary made a career change, moving from the management of international businesses in the banking sector to become CEO of UICC based in Geneva, Switzerland.
RESOURCES www.uicc.org /uicc /uicc.org/
Striking a balance: engineering effective live vector vaccines Professor James E Galen, PhD, is a Professor of Medicine at the Center for Vaccine Development at the University of Maryland School of Medicine. He is a passionate genetic engineer whose work to date has focused on vaccine development. Most recently, he has turned his attention to live vector vaccines, which offer promise for tackling prevalent bacterial infections without the use of antibiotics.
Novel Drug Development
How does a live vector vaccine differ from other vaccines? Live vector vaccines are made from bacteria that have either been engineered to be non-pathogenic (such as attenuated S. Typhi bacteria) or from non-virulent bacteria such as Escherichia coli. Once the vaccine strain is available, we can then take it to the next level. We further engineer the original vaccine to deliver additional vaccine antigens (such as smaller pieces from TcdA, TcdB, and Cdt) that the original vaccine strain would not normally produce. Essentially, we are replacing the needle often used for vaccinating people with proteins (think hepatitis B vaccine), with a living bacterial organism capable of delivering the desired vaccine antigens to the immune system. How easy is it to find a balance between attenuation and immunogenicity? Although I would love to convince you that I have finally figured out how to do this… I’m not sure yet. Only clinical trials with our best candidates will prove whether we got it right or not. The key concept to appreciate here is that finding the right balance on paper is easy; getting it to actually work in a human being is a much more daunting, but far more interesting, challenge. What is the most exciting aspect of your research? I have had the privilege of participating in the design and construction of a live vaccine against the human pathogen Vibrio cholera, testing it in animals, watching this vaccine become approved by the Food and Drug Administration (FDA) for clinical testing, then actually handing a cup of vaccine to a fellow human being,
ntibiotic-resistant bacteria (ARB) threaten the treatment of bacterial diseases. The over-use of antibiotics significantly increases the incidence of ARB and of disease.
Clostridium difficile is a bacterium that particularly affects the elderly, especially after treatment with antibiotics for unrelated infections. Infection causes diarrhoea and can cause colitis. Recurrent strains are more infectious and once it has recurred, patients are more likely to suffer from the infection again (i.e. it is more likely to keep coming back). Antibiotic resistance causes C. difficile to be more prevalent and recur more frequently.
watching that person drink the vaccine, and finally finding out that the resulting immune response was fabulous. Through the heroic efforts of my mentor, Dr Myron Levine, this vaccine was actually licensed in the United States (read more here). This just doesn’t happen that often in a scientist’s life. If I could see such a thing happen with a live carrier vaccine against C. difficile, I would be “over the moon”. Has your experience as a technician as well as an academic helped you in your work? My journey to full Professor has been unorthodox at best. But I have always been grateful to have worked both as a technician and PhD in both academia and industry. Academia taught me how to think critically and to read the literature before doing the experiment. But industry taught me something just as valuable: the value of time. Tomorrow is for the next experiment, not the one that should have been completed today. Where do you see this line of research going next? I would like to see an optimised live carrier vaccine progress through clinical trials and be proven to be safe and protective against disease. It does not actually have to be my vaccine that makes it through clinical trials and succeeds. I would be grateful to have contributed in some way to the proper engineering of the right live vaccine, and would be thrilled to see this important vaccine strategy be proven useful and valuable to the field of vaccinology. I would like to see carrier vaccines proven to be as useful as injectable vaccines, at least in cases where vaccination against mucosal diseases is required.
PREVIOUS WORK Studies characterising the genome of C. difficile reveal that three toxins are frequently found, sometimes together, in hyper-virulent strains. These toxin proteins are referred to as ‘virulence factors’: molecules produced by an organism like a bacterium that affect its pathogenicity, or its ability to cause disease. The main virulence factors in C. difficile are called TcdA and TcdB. They are usually found together in epidemic strains, which suggests that they cause disease when they are co-expressed. These enterotoxins, as they are called, cause cells to swell and burst (apoptosis), and disrupt the cell structures, both key features of conditions like colitis,
Novel Drug Development
to which C. difficile is linked. An additional toxin, Cdt, also enhances the virulence of C. difficile and causes the bacteria to adhere better to the intestinal wall. DEVELOPING A VACCINE If these virulence factors that cause C. difficile to be more virulent can be targeted by immune responses, then the risk of infection and recurrence can be reduced. Animal models show that this has been effective. Treatment with a vaccine is preferable to antibiotic treatment because antibiotic resistance is the reason that C. difficile thrives and recurs. Professor Galen and his team are developing live vaccines that provide immunity to disease by stimulating an immune response using safe doses of antigens (smaller parts of the toxins that stimulate an immune response, e.g. TcdA, TcdB, and Cdt). The vaccine will initially be given to people already infected with C. difficile. The team hypothesise that this will trigger a response to the bacteria because the immune system has already encountered it, and will be able to produce antibodies to fight off the infection (an anamnestic response). PICKING YOUR TARGETS Evidence from animal models suggests that targeting immunity to inactivate the toxins TcdA and TcdB, as well as also targeting the binding ability of Cdt to enhance the adherence of C. difficile to cells, would be successful in blocking recurrence. There is clear evidence that the antibody immunoglobulin G (IgG), capable of binding to and inactivating the toxins from C. difficile, is linked to resistance to disease. However, simply eliciting an antibody response does not always work. Moreover, research suggests that targeting enterotoxins alone is not always effective. Therefore, to increase the chances of success, the vaccine must target Cdt as well. Galen has therefore proposed a three-prong approach which will hopefully target the different toxins present in C. difficile in different ways: firstly, the toxins are prevented from binding by triggering a serum antibody response (serum is the protein-rich, liquid component of blood) and therefore generating immunity; secondly, immunity is induced in the intestinal mucus, which reduces the ability of Cdt to bind to intestinal cells; thirdly, mucosal immunity is targeted to reduce colonisation, recurrence and transmission.
... simply eliciting an antibody response does not always work. Galen has proposed a three-prong approach which will hopefully target the toxins present in C. difficile in different ways FINDING A CARRIER To be able to vaccinate against C. difficile, Galen’s team has had to find an appropriate carrier, or vector. Galen and others have already used carriers derived from Salmonella enterica serovar Typhi effectively in animal models, for instance against plague. There are substantial benefits to using S. Typhi as a carrier: it can be delivered orally, targets specific immunity cells where vaccines are more likely to be effective, and can stimulate broad immune responses. However, to make S. Typhi safe for use as a carrier vaccine in humans, virulence factors from S. Typhi must be genetically removed to avoid producing disease, while still preserving the ability to deliver antigens from C. difficile. The resulting safe carrier is then engineered to express smaller, non-toxic pieces of the two enterotoxins TcdA and TcdB that cause C. difficile to engender an immune response. GETTING THE BALANCE RIGHT However, finding the balance between attenuation (reducing the virulence of a pathogen like S. Typhi, while still keeping it ‘live’) and immunogenicity (the ability to provoke an immune system response) is essential. If the carrier vaccine is not properly weakened, it can cause adverse clinical effects. However, if the vaccine is too weak, and doesn’t provoke an immune response (its reactogenicity, or ability to cause expected adverse effects, is minimal), immunity is not developed. Essentially, you don’t want the attenuation to be too effective; otherwise it defeats the purpose of vaccinating in the first place. IT’S ALL IN THE METHODS Developing a live vector vaccine is complex, and the methods employed to incorporate antigens are important. In a recent review paper [Galen & Curtiss] Professor Galen put it this way: “The manner in which these antigens are delivered to the immune system can have a profound effect on the resulting immune responses and ultimate success of a carrier vaccine”.
There are two main ways of genetically engineering a suitable carrier vaccine candidate. Firstly, scientists can use plasmids, circular types of bacterial DNA that differ from linear chromosomal DNA. Plasmids can be used to introduce new genetic material (such as genes capable of making antigens from C. difficile) and alter the expression of the carrier. However, this can cause metabolic stress that triggers selective plasmid loss, minimising its effectiveness. Additionally, plasmid methods can often lead to over-attenuation, making the vaccine less powerful. The second method irreversibly inserts antigen-encoding genes directly into a single location within the chromosome of the candidate live vector without any further need for plasmids. The problem with the chromosomal approach is that the amount of antigen made is often much lower than levels made using plasmids. However, one study [Wang et al] found that inserting genes in two locations on the chromosome, rather than just one, yielded results that were far better. They also found that foreign antigen synthesis could be “tuned” to the physiology of the carrier vaccine, a competitive advantage. LOOKING AHEAD So far, no human trials have been carried out with vaccines that get the balance right between attenuation and immunogenicity. The logical next step is therefore to do this with optimal live vaccines. Building on the success of previous work, an effective vaccine may soon be available for prevention of many bacterial diseases for which treatment with antibiotics is becoming less effective. The technology developed in recent years by Galen and his team may even have future applications in oncology: engineered reagents may be able to promote tumour reduction in certain types of cancer.
Detail RESEARCH OBJECTIVES Professor Galen’s work focuses on the development of live vector vaccines and their importance in the fight against antibiotic resistance. His current project aims to create a live vector vaccine for use against the increasingly resistant bacteria, Clostridium difficile. COLLABORATORS • D r Jan ter Meulen (Merck) • D r Jimmy Ballard (University of Oklahoma) • D r Hanping Feng (University of Maryland Dental School) BIO Professor James E Galen is a genetic engineer with over 20 years’ experience in both industry and academia. Starting out as a technician, he became Research Assistant to Dr Jim Kaper before earning his PhD from the University of Maryland Baltimore. After two years as a Research Scientist at MedImmune he moved to a faculty position at the Center for Vaccine Development. Here, he continued to focus on live vector vaccine development, contributing to significant advances in both vaccine development and innovative methods for testing the immunogenicity of candidate vaccine strains. Now Head of the Salmonella Live Vector Vaccine Unit, Prof Galen enjoys the teaching and mentoring element of his role as well as his research efforts. CONTACT Professor James E. Galen Chief, Salmonella Vaccine Section Center for Vaccine Development Division of Geographic Medicine University of Maryland School of Medicine Health Sciences Facility, Room 480 685 West Baltimore Street Baltimore, Maryland 21201-1509 E: firstname.lastname@example.org T: +1 410 706-6995 W: http://medschool.umaryland.edu/ facultyresearchprofile/viewprofile. aspx?id=2357
Resistance is futile: hybrid drugs become the latest weapon in the biological arms race Researchers at DesignMedix, led by Dr David Peyton, have successfully combined two bioactive compounds to restore the effectiveness of an anti-malarial drug neutralised by the emergence of resistant strains. Their work is paving the way for a new approach to combatting the growing problem of drug resistance.
Novel Drug Development
What led you to look into chemical synthesis as a means of overcoming drug resistance? The ‘gold-standard’ drug, chloroquine, had been lost, at least to its traditional use, and so we had to find another way forward. The simplest and least expensive way to salvage the best features of chloroquine was to make a ‘better chloroquine’, at least better given the current state of drug-resistance across the developing world. This meant chemical synthesis, because there is no other way to get there. In your view, what are the main challenges facing the development of drugs for the emerging economies market? Bridging the ‘gap’ that exists between discovery and marketing. There are resources from agencies such as the NIH for university researchers, and even funds available through programmes (for example, the SBIR or STTR mechanisms in the US) that work quite well at the early stages. But it becomes more challenging to bridge the efforts as they become more expensive and depend on resources that are not internal to universities or small businesses, such as GLP service providers. These can be unfamiliar to traditional researchers and relatively expensive, making it challenging for the usual grant mechanisms to fund fully. Then, there is the obstacle of bringing the drug through the human trials – which will require teams and financial resources that are well beyond what almost any researcher originally involved in the enterprise of drug discovery would have thought about. For malaria, there are entities that can help, but that is less true for other markets.
What makes you confident that malaria will eventually be eradicated? That is a very large question. I am confident that malaria can be eradicated. I am confident that malaria will be eradicated just as long as sufficient resources are dedicated to the effort for as long as it takes. I also believe that this is a very serious topic, and that we should not make the mistake of making it seem easier to do this than it will be. Unless there are some unforeseen developments, the eradication effort for malaria will take decades and constant dedication. But it will be worth it. The alternative is continual evolution of resistance against each generation of newly-developed tools. What would make the biggest difference to the successful development of DM1157? Partnering with a company with another drug in its pipeline, such that these drugs make sense as a combination to move through the next stages of the development and approval process. Hopefully, such a company would have the resources or connections to facilitate marketing throughout the developing world populations where malaria drugs are needed. What one piece of advice would you give to someone considering creating a start-up? Don’t do it by yourself. A scientist needs help with the ‘business side’ of the process, and everything you do takes time. Without my partners in this enterprise, I’m sure we would have not made the progress we have.
The eradication effort for malaria will take decades and constant dedication. But it will be worth it 45
Novel Drug Development
alaria is a devastating disease which disproportionately affects emerging economies: it is estimated to cost African nations alone $12bn a year in healthcare costs and loss of economic output. This is compounded into the perfect storm when low-cost treatments are rendered ineffective due to the evolution of resistance in parasite populations. The search for novel therapies and other control methods is ongoing, but Dr David Peyton from Portland State University (PSU) is refusing to surrender in the battle against drug resistance. With an academic career at PSU which focussed initially on heme proteins, antigenâ€“antibody binding, and virus particle formation, Dr Peyton naturally became involved with public health. On moving to the study of medicinal chemistry, with a particular interest in malaria treatment, he came across the issue of drugs lost to evolved resistance and developed a unique approach to combat the phenomenon. Determined that chloroquine, the safest and least expensive drug to be used against the malarial parasite, should not be lost, Dr Peyton set out to re-engineer the compound to overcome the parasiteâ€™s evolved ability to eliminate the drug. Chloroquine diffuses into the acidic digestive vacuole of the parasite during the asexual stage of its life cycle, when it is within red blood cells degrading haemoglobin for nutrition. In the acidic environment of the digestive vacuole, chloroquine undergoes protonation: because acidity is effectively the number of free protons (H+) in a solution, some molecules will accept these free protons and be changed as a result. As well as the obvious changes in charge and mass from accepting another proton, many chemical attributes of the molecule may also be changed. In the case of chloroquine, these chemical changes mean that it can no longer diffuse back out of the digestive vacuole the way it came in and it builds up, preventing the parasite from eliminating the toxic by-products of haemoglobin metabolism. THE RISE OF RESISTANCE Due, at least in part, to the use of mass drug administration as a method of controlling malaria in areas with high endemicity (high levels of the disease), selective pressures have resulted in the emergence and spread of drug-resistant strains. Mutations in a particular transmembrane protein effectively
DM1157 returns a tool with chloroquineâ€™s advantages to its previous status as a low-cost and effective weapon in the fight against malaria render chloroquine useless as a treatment. The transmembrane protein is responsible for exporting chloroquine out of the digestive vacuole and the key mutation results in a significant increase in efflux efficiency (how quickly chloroquine is removed). The P. falciparum chloroquine resistance transporter (PfCRT) has been found to be 40-50 times more effective at removing chloroquine from the digestive vacuole in mutated versus original strains. It is thought that this protein may be using the proton gradient across the vacuole membrane to drive the export of the protonated form of chloroquine. Dr Peyton and his team hypothesised that, by linking a known inhibitor of the transmembrane protein to the chemical skeleton of chloroquine, they could create a revitalised version of an established treatment. The parasite would once again be unable to eliminate the drug and it could form the basis of new mass
administration and/or targeted programmes, this time using combination therapies to reduce the likelihood of evolved resistance. The challenges involved in this are significant, however, as any new compound needs to tick all the boxes on the malarial treatment wish list. It must be stable at tropical temperatures to allow for cheap transport and storage in the countries where malaria is endemic. Similarly, with oral dosing as the preferred route of administration for public health programmes, aqueous solubility is of prime importance. But perhaps the most challenging of all, and one of the reasons investment in this area is lacking, it must still be of sufficiently low cost to make it economically viable for healthcare services in developing countries. Confident of their abilities to overcome these hurdles, the team spun out DesignMedix, Inc. a start-up
Detail RESEARCH OBJECTIVES: Dr David Peyton uses pioneering techniques to restore the effectiveness of drugs. His work focusses on low-cost, safe treatments for malaria. FUNDING • NIH:NIAID • ONAMI (Oregon Nanoscience and Microtechnologies Institute) [http:// onami.us/] COLLABORATORS •D r Michael Riscoe, Portland VA Medical Ctr and OHSU •D r Jane Kelly, Portland State •D r Roland Cooper, Dominican University of California •D r Jutta Marfurt and Dr Ric Price •D r Steven Burgess •D r Lynn Stevenson and Dr Sandra Shotwell, co-founders of DesignMedix, Inc. [http://www. designmedix.com]
focused on using this technique to resurrect previously effective treatments. With support from the National Institutes of Health and colleagues at PSU, an arsenal of new compounds was developed and each one tested against the malarial parasite. There are a number of suitable candidates for inhibition of the transmembrane transport protein responsible for the efflux of chloroquine. Known as reversal agents (because they reverse resistance to a drug) they include verapamil, a drug used in the treatment of heart disease and hypertension, and the anti-depressant imipramine. These chemicals are among a large group known to have the right chemical structure to interact in this way with the mutated protein and imipramine was chosen by the team as being particularly suitable for attachment to the chloroquine molecule. Through a small number of simple reaction steps, chloroquine can be restructured to become essentially a hybrid with imipramine, prepared as a free base, or converted to a hydrochloride (or other) salt to promote water solubility. A NEW WEAPON EMERGES From more than two hundred similar compounds (termed ‘reversed chloroquines’)
created in this way, one was selected. Given the title DM1157, this novel chemical has been put through its paces in in-vitro and exvivo studies, as well as having proven efficacy in mice. These impressive results mean it is now ready for its first in-human clinical trials, as it forges a new path to return a tool with chloroquine’s advantages to its previous status as a low-cost and effective weapon in the fight against malaria. With the right support, the success of DM1157 could open the way for the same approach to be used across a range of treatments and pathogens, potentially returning many drugs to therapeutic use. Malaria remains a devastating disease across much of the developing world, preventing many emerging economies from realising their full potential. In spite of intense research efforts and new control methods, the fight against this destructive protozoan will continue to need novel tools in the shape of drugs, insecticides and perhaps even vaccines. DM1157 will be one such weapon which, in combination therapies with other effective treatments and alongside public health programs, could give us the upper hand in the battle for eradication.
BIO After a PhD at UCSB in 1983, and postdocs at Weill Cornell Medical College and UCD, Dr David Peyton began his academic career at PSU, focused on heme proteins, antigen–antibody binding, and virus particle formation. He then moved into medicinal chemistry to study malaria and co-founded the company DesignMedix, Inc. He also studies the toxicology of tobacco products, including e-cigarettes. His career has thus become concerned with public health. CONTACT David H. Peyton, PhD Room 323B SB-1 (office behind lab) Professor of Chemistry Portland State University Portland, OR 97207-0751 E: email@example.com T: +1 503 725 3875 W: https://www.pdx.edu/profile/davidpeyton http://www.designmedix.com For more information on malaria visit: https://www.niaid.nih.gov/topics/ malaria/Pages/default.aspx
Planting Seeds of Hope New drug production method could provide affordable, safe treatment for stroke victims Dr Kevin Yueju Wang and his team, from Northeastern State University, focus their research on the sustainable, low-cost production of drugs to treat stroke victims. They are pioneering the use of transgenic plants to produce drugs that dissolve stroke-causing blood clots.
Novel Drug Development
Why is it preferable to use plants (rather than mammalian cells) to produce drugs? Plants can be grown and maintained at much lower cost than bacteria, yeast or mammalian cells. This means initial studies can be done with a lower financial investment. Additionally, once created, the source (leaves or seeds) is potentially unlimited. They are also preferable to other types of cell in terms of cost, safety and the speed of production. They are able to produce the complex proteins that are required, including antibodies. Unlike mammalian cells, there is also no risk that the drug will become contaminated by animal pathogens, for example viruses. This is a huge boost for the safety of these drugs. Read more: http://www.ncbi.nlm.nih. gov/pubmed/26633378 Can you give a brief overview of how these plants are genetically modified? We identified potential genes (DSPAÎą1 and tPA) suitable for plant-based protein development. Both genes were synthesised and cloned in a plant gene expression vector. Both genes were driven by seed-specific promoters, which target expressed proteins only in seeds. The tobacco leaf discs will be transformed using the natural genetic engineer, Agrobacterium tumefaciens. The shoot grown from a single cell containing foreign genes will be screened by molecular techniques, and then selected for producing seeds. Proteins from seeds will be extracted and purified. They will then be used to dissolve fibrin and blood clots. What are the challenges of using transgenic plants to produce drugs? The field of using transgenic plants for pharmaceutical drugs is relatively new and, as such, there are not many existing protocols for us to follow. Each plant species is made up of unique sets of proteins and metabolites so the purification process is also unique for each species. The complexity of the plant make-up means that designing a purification
method (to isolate the proteins produced by the transgenic plant) is very complex. In addition, crops grown in fields (like wheat or rice) raise cross-contamination concerns: the pollen from the transgenic plant may contaminate normal plants that are being grown nearby. Currently, the use of food crops for the production of recombinant pharmaceutical compounds (made using transgenic plants) is restricted. Tobacco is an excellent candidate for pharmaceutical production. It is not a food crop and has a simple gene transfer system. The plants can be produced in just six months and both the leaves and the seeds can be used for production. The systems for ensuring biosafety and the processes for purification have both been established for tobacco. Read more: http://www.ncbi.nlm.nih.gov/ pubmed/26633378 Are there any other natural anticoagulant protein sources that can be used to treat stroke? There are currently no effective anticoagulant proteins used to treat stroke. Some thrombolytic agents are available to prevent stroke. These include, among others: streptokinase, secreted by several species of streptococci; urokinase, found naturally in humans, especially in urine; nattokinase from fermented soybeans, a dish known as natto; and lumbrokinase from earthworms. We are working on using plants to produce these anticoagulant proteins. How do you plan to develop your research in the future? For current tPA or DSPAÎą1, we are refining the purification process. We expect to produce proteins with 99.9% purity for our pre-clinical safety test. In the future, we will conduct clinical trials and put the proteins into clinic usage. We will discover more candidate genes that meet a commercial need. We will develop a good production system and build a bridge between basic research and its commercial applications.
Novel Drug Development
trokes are a severe and lifechanging disease. Not only do they cause 15 million deaths per year worldwide, they also have potential long-term consequences for survivors, including impaired vision and mobility, dementia and depression. Unfortunately, the incidence of stroke is increasing as the global population ages. In order to combat this devastating disease, the development of cheap, efficient drugs is vital and Dr Wang's team is currently focussed on achieving this goal. CAUSES OF STROKE During an acute ischemic stroke (85% of cases), arterial blood clots reduce the flow of blood to the brain. Brain cells, starved of oxygen and essential nutrients, rapidly deteriorate and die. There are two key components of a blood clot: aggregated platelets and a structural mesh of the protein fibrin. Currently, acute ischemic strokes are treated using a medication called alteplase, otherwise known as tissue plasminogen activator (tPA). This enzyme breaks down fibrin, destroying the blood clot and restoring blood flow to the brain. Currently, alteplase is the only Food and Drug Administration (FDA) approved drug for the treatment of acute ischemic stroke. However, there is much debate regarding the effectiveness of alteplase – Dr Wang draws attention to its high level of side-effects in particular. Research has shown that alteplase must be taken within 3-4.5 hours of a stroke occurring. Any delay increases the risk of severe side effects such as neurotoxicity, brain damage or potentially life-threatening haemorrhage. Stroke victims frequently do not seek emergency treatment within this opportunity window meaning that alteplase cannot be used as a treatment for the vast majority of stroke victims: it is currently only administered to around 2% of patients. VAMPIRE BAT SALIVA – A BETTER DRUG? The natural world has often provided inspiration to those looking to solve human problems and, after much research, scientists discovered that the proteins found in vampire bat saliva could provide a significantly more effective and safer therapeutic option for treating stroke than alteplase. Vampire bats prey on other mammals, feeding on their victim's blood. To enable continued feeding, vampire bats have
In comparison to mammalian-based systems, the use of transgenic plants is significantly cheaper and safer, as there is a reduced risk of contaminating the drug with pathogens evolved mechanisms to delay clotting and so prolong bleeding. For example, their saliva contains anticoagulants, including the proteins, Desmodus rotundus (vampire bat) salivary plasminogen activators, or DSPAs. Although there are several types of DSPA, the majority of studies focus on DSPAα1 for treating ischemic stroke. Dr Wang and his team have decided to carry out their research using both DSPAα1 and DSPAα2 – a little studied DSPA that the team’s preliminary work shows also attacks clots. DSPAα1 can bind more tightly to fibrin than alteplase, increasing its efficacy. Additionally, DSPAα1 can be administered up to 9 hours after a stroke, greatly increasing the number of people who can be treated. It is also relatively safe: unlike alteplase, DSPAα1 does not act on certain brain cell receptors, meaning there is less risk of brain damage, and it has not been seen to cause overbleeding.
However, further testing, such as animal trials, is required before DSPAα1 is considered safe for therapeutic use. THE CHALLENGES OF CURRENT DRUG PRODUCTION Currently, mammal cells are used to produce alteplase on an industrial scale. If DSPAα1 was in wide-spread use today, it would also be produced using these methods. These mammal cells are used because they are like minuscule factories – capable of constantly producing new proteins. By manipulating these cells using 'recombinant technology', scientists can programme the cells to produce the desired alteplase protein. 'Recombination' involves combining DNA from different organisms to produce a new protein. In the case of drug production, the section of DNA that codes for alteplase is
inserted into the mammal cell genome. This mammal cell is now 'transgenic'. The alteplase protein (tPA) is therefore expressed in the mammal cell. After filtration and purification of the tPA from the other cellular components, it is then ready to be developed into a drug. However, using mammal cells as a way of producing drugs on a large scale has several major disadvantages. For example, production is very expensive – in 2014 a dose of 100mg of tPA cost around US $6,400! Additionally, this technology is low-yielding and the risk of cell culture contamination (for example, through viruses that use mammal cells as host cells) is high. Dr Wang and his team have developed an innovative method to overcome these challenges by using plants to produce both tPA and DSPAα1. PLANTS AS DRUG FACTORIES Scientists and drug companies are viewing plants in a new light – as effective and sustainable pharmaceutical factories. For example, by using transgenics, the tobacco plant, which, paradoxically, is responsible for causing many deaths worldwide, has been used as a tool to produce drugs that fight deadly diseases, including malaria. Inspired by this research, Dr Wang has developed tobacco plants to produce seeds
that contain DSPA or tPA. In a similar way to mammalian-based production systems, Dr Wang used 'recombination technology'. The team combined the DNA of DSPA with a 'seed-specific promoter'. This means that the DSPA is only made in the seed and not in any other part of the tobacco plant. These plants are then grown and cultivated in a greenhouse, the seeds are collected and the desired protein is isolated.
KEY ADVANTAGES There are several reasons why seeds (instead of other parts of the plant) were selected as the drug-producing site. Firstly, there is a reduced risk of protein degradation in the seed compared to other locations such as the leaves. This means that there is less chance that the drug will be broken down before it is harvested. Additionally, seeds produce unlimited generations of drug-producing tobacco plants, so the potential yield is very high. Seed can produce recombinant protein at high yield and maintain protein stably at room temperature up to several years. Most seeds can be subjected to a surface ‘sterilisation’ without damage to the proteins.
FUNDING • N IH – National Institute of Neurological Disorders and Stroke • N IH – National Institute of General Medical Sciences
In comparison to mammalian-based systems, the use of transgenic plants is significantly cheaper and safer, as there is a reduced risk of contaminating the drug with potentially dangerous animal viruses and other pathogens. Furthermore, due to the high yield of plant-based systems, the cost of the resultant DSPAα1 or alteplase (tPA) is much cheaper – an estimated cost of around $450 per dose for either treatment. WHAT DOES THE FUTURE HOLD? Even though tPA has side effects, it is still the only drug approved for acute ischemic stroke. We can use plants as an alternative production system to produce tPA at low cost. In order to fight stroke safely and effectively, it is also imperative that we develop better drugs than tPA. Research has shown that DSPAα1 from vampire bat saliva meets these demands as a safe alternative that can be used to treat a larger number of patients. In addition, Dr Wang has shown that, by using transgenic plants rather than mammalian-based systems, we can produce these drugs both cheaply and efficiently with a high, sustainable yield. The hope for the future of this research is that DSPAα1 production by transgenic plants will be commercialised, enabling significantly more people to be saved from the devastating consequences of stroke.
RESEARCH OBJECTIVES Dr Kevin Yueju Wang targets recombinant proteins in plant seeds for the treatment of stroke patients. Seed platforms can be used to produce a variety of active, safe, and inexpensive therapeutic proteins.
COLLABORATORS • H angzhou Funiu Pharmaceutical Biotech Ltd. • J iayi (Joy) Cheng BIO Dr Kevin Yueju Wang is an Associate Professor at the Northeastern State University. His team are applying transgenic plants for production of human therapeutic proteins on a large scale at low cost. CONTACT Department of Natural Sciences Gregg Wadley College of Science & Health Professions Northeastern State University 3100 E. New Orleans Broken Arrow, OK 74014, U.S.A. E: firstname.lastname@example.org T: +1 (918) 449-6479 W: https://www.nsuok.edu/directory/ profile/wang03.aspx FOR MORE INFORMATION VISIT • http://www.kjrh.com/news/ local-news/northeastern-stateuniv-research-finds-affordablealternative-to-combat-stroke-effectswith-bat-dna • https://www.youtube.com/ watch?v=HMAdVAAJ33c • h ttps://www.google.com/patents/ WO2016118732A1?cl=en
One Mind - IMHRO Opening up discussions on brain health Garen Staglin, Co-founder and Chairman of One Mind and Co-founder, President and Trustee ofÂ IMHRO/One Mind Institute, emails Research Features to tell the story of how his organisations are opening up discussion on brain health to combat stigma and provide support.
How would you describe your role and responsibilities at One Mind and IMHRO? Motivated by the psychotic break of our son, Brandon, my wife Shari and I co-founded the International Mental Health Research Organization 22 years ago. In 2011, with former Congressman Patrick Kennedy, we founded One Mind for Research to accelerate treatments and cures for all brain disorders. I serve as Chairman of both organisations, and I directly interact with scientists and leaders of research organisations as well as donors globally.
host an annual One Mind Summit to bring neuroscientists together to break down the â€œsilosâ€? of research, and foster collaborations. We also host an annual Music Festival for Brain Health which brings more than 500 people together to learn about the latest breakthroughs in neuroscience and celebrate and support research. We also co-founded Bring Change 2 Mind and produced a PSA (public service announcement) to reduce stigma. Our social media presence is another active way we promote dialogue and awareness.
Your family has shared personal experiences in order to help others and raise awareness. How important do you feel it is to keep the mental health conversation flowing? As public advocates for brain health, we are constantly called on by parents and advocates to find available psychiatric care, and to support awareness programmes. We
Each year, IMHRO offers Rising Star Awards of up to $250,000 for research to improve understanding and find therapies for mental illness. Your finalists for this year have now been notified, are you able to tell us anything about them and their projects? IMHROâ€™s Scientific Advisory Board has chosen Drs Mazen Kheirbek, PhD, and Mary
Kay Lobo, PhD, to receive the 2016 IMHRO/ Janssen Rising Star Translational Research Awards, and Dr Kate Fitzgerald, MD, to receive the 2016 IMHRO/AIM Sullivan Family Foundation Rising Star Award. Full details of each research project can be found here.
We host an annual One Mind Summit to bring neuroscientists together to break down the “silos” of research, and foster collaborations
The IMHRO Rising Star awards encourage the community of researchers to direct their efforts toward translational science while supporting the research of emerging leaders in the field. They also fill a critical gap of support as federal funds dedicated to research continue to decline. The 2016 Rising Star Award winners were selected with the assistance and recommendations of the IMHRO scientific advisory board, which includes ten of the leading brain scientists in the world, noted for their pioneering research in their respective fields. Each Rising Star recipient will receive $250,000 to fund research for his or her studies.
important education projects: • U sing youth in videos, blogs, and social media to explain what psychosis is, why early intervention can be helpful, and what the warning signs are. • P artnering with the Northwell Health Early Treatment Program to produce a zip-code targeted social media campaign which serves up ads when “terms” suggesting psychosis are searched for so that treatment can then be provided. The goal is to dramatically reduce the time of untreated psychosis.
One of your recent projects, Partners for StrongMinds, has a mission ‘to transform the way that psychosis is detected, treated and understood in the United States’. What are their strategies for improving psychosis health care? Their strategies are demonstrated in two
One Mind has partnered with a pioneering online patient community builder, PatientsLikeMe. What do you hope users will gain from this innovative tool? The PatientsLikeMe portal was designed to create a “community” where patients in
the 3000-person, multi-site, longitudinal study on traumatic brain injury (TBI) can communicate with others, in addition to allowing new participants to discuss all aspects of their lives with TBI. There are now more than 16,000 participants, with more than 30% also presenting posttraumatic stress (PTS). We expect this “community” to be a future recruitment source for clinical trials or novel therapeutics. IMHRO is currently funding research into digital tools to “real time” monitor schizophrenic patients' prognoses and responses to treatments. How do you think this could help future clinicians? Digital health and mobile monitoring hold the promise of using data on sleep, social interaction, voice tones, blood pressure, and other signs, in order to give data
Detail INTERVIEWEE BIO: Garen is a private investor and philanthropist, with 40 years’ experience in the financial services and transaction processing industries. He has served on numerous public company and private boards, and cochairs the $4.2 Billion UCLA Centennial Campaign. Together with his wife, Shari, CEO, and Shannon, President, and Brandon, Communications Director, they operate the acclaimed Staglin Family Vineyard in Rutherford, Napa Valley, California.
on disease progression and therapeutic effectiveness. We expect to use these capabilities in a study involving 17 counties in CA, as well as the 100,000-person cohort being launched at UCLA for depression. What are IMHRO and One Mind’s future goals? • Continue to push “open science” and eliminate the silos of research that retard progress in all aspects of neuroscience research. • Continue to support public/private partnerships that bring researchers, pharma, and the FDA into large-scale studies that have scale and outcomesbased metrics for success. • Continue to bring new sources of private philanthropy to brain disease research. • L aunch of global leadership initiative to bring “gold standards” of behavior to corporations, academic institutions, and governments for people with brain diseases – much like exists for cancer through the CEO Cancer Roundtable. • E xplore the possibility of a “social impact” bond to fund brain research on a global level issued by either the US Treasury or the World Bank.
Within the field of mental health research, what do you hope to see achieved in your lifetime? • S mall molecule therapies directed to genetic mutations for all psychiatric disorders. • P erfecting innovative therapies that capitalise on brain plasticity • D igital health advances and mobile monitoring that accurately predicts disease progression and therapeutic effectiveness. What are your proudest achievements to date for One Mind and IMHRO? Many accomplishments come to mind, for instance, raising more than $250 Million in direct and “leveraged” funds for research. Also, we have funded 24 Rising Stars who have gone on to greatness. One, Josh Gordon, was just named the new Director of NIMH. Another achievement would be One Mind’s Project Gemini, a global study for TBI and PTSD that has already discovered a biomarker which is under review for FDA approval in record time. I am also particularly proud of the hope and awareness that we have brought to the thousands of people who suffer from a brain disease, as well as the slow but steady reduction in stigma.
ORGANISATION BIOS: IMHRO is committed to raising awareness and funding research to find preventions and cures for schizophrenia, major depression, and bipolar disorder within a generation. IMHRO is led and supported by families and individuals whose lives have been touched by brain disorders - and who have seen how far mental health research has come in the last decade. Contributions to IMHRO and ONE MIND™ have resulted in more than $256 million for research, changed thousands of lives, and funded stunning discoveries for better therapies now and tomorrow. www.imhro.org ONE MIND™ is a new-model non-profit organization that is taking the lead role in the research, funding, marketing, and public awareness of mental illness and brain injury, by bringing together the governmental, corporate, scientific, and philanthropic communities in a concerted effort to drastically reduce the social and economic effects of mental illness and brain injury. With ONE MIND™ as the hub for openscience, big data, and research, compelling the scientific, health care, and pharmaceutical communities to collaborate completely for the common good, we can accomplish what would have previously required 50 years in less than a decade. www.onemind.org @IMHRObrain /imhro/
Investigating targets for a new class of anti-HIV drugs Despite effective combination therapies that can suppress viral infection, there is an urgent need for the discovery of a new class of anti-HIV drugs as the virus is increasingly developing resistance to current treatments. Dr Debnath and his team have focused on the structure of the binding site between the virus and host cells that is critical for the establishment of infection. They have therefore been working on small inhibitory molecules targeted at this site and have identified several promising candidates suitable for further drug development leading to a new class of anti-HIV therapeutics.
Novel Drug Development
What made you take the move into studying the gp120-CD4 binding site in the search for new antiviral drugs? The 1998 discovery by Dr Peter Kwong of a cavity in the gp120, termed Phe43 cavity, in the X-ray structure of CD4gp120-17b provided the initial motivation. It prompted us to study this site in early 2000 as a target for novel anti-HIV-1 drug discovery because it was a novel target and no one, as far as we know, had attempted to target that site using small molecule inhibitors. In addition, there is no drug approved yet that targets this binding site. How important has collaborative work been for furthering your discoveries in the field? We realised that the discovery of drugs using a structure-based approach is a complex multi-disciplinary undertaking and collaboration with leaders in this field is key to any success. All our major discoveries so far have been the result of successful collaborations with Dr Peter Kwong’s group in structural biology at the Vaccine Research Center, NIH and Dr Andrea Altieri’s group in medicinal chemistry at Edasa Scientific, Russia.
r Asim K Debnath has been conducting research on antiviral drug design for the past two decades and is head of research at the Laboratory of Molecular Modeling and Drug Design in the Lindsley F Kimball Research Institute, New York Blood Center. Using state-of-the-art drug design methods, his team's main goal is to identify new antiviral drugs effective against viral cell entry and assembly of human immunodeficiency virus type 1 (HIV-1). The laboratory’s current projects are funded by the National Institute of Health (NIH). HIV-1 is the virus responsible for the AIDS pandemic. The infection is global with a similar rate of infection in several major
How far has research following your discovery of a broad-spectrum inhibitory drug progressed towards developing an available treatment for HIV-1 patients? Admittedly, there is a lot more work to do before this class of drugs will be available to treat HIV-1 patients. However, we are hopeful that with continued financial support we will be able to achieve our goal. What avenues of your research could hold the most promise in developing a cure for HIV-1 infection? A successful discovery of a combination of latency reversing agents (LRAs) that can efficiently help expose HIV-1 surface proteins on latently infected cells, along with an effective design of antibody drug conjugate, may help in achieving a functional cure for HIV-1 infection. How do you see your research progressing over the following years? We expect to start early clinical studies of our gp120 targeted drugs in the next 4–5 years.
US cities to some sub-Saharan African countries. Currently, viral replication can be controlled for extended periods of time using drugs that target viral enzymes (reverse transcriptase, protease and integrase) and viral entry (gp41 and cellular receptor CCR5), but there is no known cure. Strains of HIV-1 are increasingly developing resistance to drugs used in combination therapies; there is a serious need for new antivirals in order to combat the growing threat posed by these resistant infections. For the next generation of antivirals to stand the best chance of combating the virus’s rapidly evolving resistance, it is important that they do not target similar viral components as existing drugs.
Novel Drug Development H3C H3C H3C H3C
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EVADING IMMUNE DEFENCES TO MEDIATE CELL ENTRY Viral entry into a cell begins when the HIV-1 envelope glycoprotein, gp120, interacts with a receptor on the surface of host immune cells, known as CD4. In the face of limited funding, Debnath and his dedicated collaborators have been carrying out pioneering research to identify small inhibitory drug molecules capable of disrupting binding of the virus to the CD4 receptor. To evade the immune response of a host cell, the envelope glycoproteins gp120 and gp41 undergo structural modifications. These allow them to avoid detection and mediate viral entry into the cell. When a viral particle binds to a host cell, gp120 interacts with the CD4 receptor on the host cell surface, resulting in conformational changes that expose particular sites of gp120. The newly exposed region then interacts with other cellular receptors which leads to the gp120-gp41 complex becoming destabilised. Once this has occurred, gp41 undergoes another structural change, initiating entry of the HIV-1 virus particle into the cell. These steps are crucial for the virus to establish infection. Due to this, the early stages of the gp120-CD4 binding process provide an ideal novel target for the development of therapeutic interventions.
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For the first time, they had discovered a new drug with the desired broad spectrum anti-HIV-1 characteristics SEMINAL DISCOVERY In their search to find new drugs that effectively target gp120, Debnath and his team carried out a targeted screen that led to the discovery of two small inhibitory molecules, NBD-556 and NBD-557. Research by another team, sparked by this finding, showed that they have a remarkable ability to mimic the CD4 receptor. This finding ignited research in the field attempting to develop inhibitors targeted at gp120, the first time drug development had focused on this target. Debnath and his group opted to take a structure-based design approach to see if they could modify this type of small molecule to produce an effective viral entry antagonist. To enable the researchers to precisely apply this approach to further develop NBD-556, in collaboration with Dr Peter Kwong at the Vaccine Research Center, NIH, they employed X-ray crystallography to uncover the structure of the NBD-556 gp120 binding complex. This revealed that NBD556 binds to a region known as the Phe43 cavity, where during gp120-CD4 binding
two similar interactions take place that are critical for viral cell entry. The NBD-556 and gp120 complex was found to possess one of these interactions but lack the other, with the amino acid Arg368gp120. NBD-556 and its analogues were also found to act as viral entry agonists, which results in increased viral cell entry, not suitable for an inhibitory drug. However, with these aspects of the molecule elucidated, they set out to improve upon the inhibitory molecule they had discovered. They suspected that it may be essential to gain the interaction they had found missing between NBD-556 and Arg368gp120, as well as needing to preserve other key interactions and develop an antagonist. STRUCTURE-BASED DRUG DESIGN The team synthesised a series of compounds based on NBD-556 with different scaffolds of basic molecular groups and tested them for anti-HIV-1 activity. These molecules were found to enhance anti-HIV-1 activity, but other tests showed that the molecules still retained the agonist properties of NBD-566.
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Detail RESEARCH OBJECTIVES Dr Asim K Debnath and his team focus on the development of novel antiHIV drugs. Their work focuses on the binding site that allows the virus to enter host cells. It is hoped that their work will lead to a new drug that will help combat the increasing resistance of HIV-1 to current modes of treatment. FUNDING National Institutes of Health (NIH)
NBD-11021 Antagonist Excitingly, among these new molecules they found one that showed reduced agonist properties, a partial agonist. This motivated the researchers to further investigate this molecule and led them to determine the X-ray crystal structure of the partial agonist bound to gp120. Their results showed that within the new molecule a basic nitrogen atom resided only 4.4 Angstroms away from Arg368gp120. However, this was not quite close enough for interaction to occur and further modification was required. DISCOVERING A NEW CLASS OF HIV-1 DRUG TREATMENTS The team succeeded in transforming the full viral entry agonist NBD-556 to a full viral entry antagonist, NBD-11021, and demonstrated that this molecule exhibits anti-HIV activity against a diverse range of viral strains. For the first time, they had discovered a new drug with the desired broad spectrum anti-HIV-1 characteristics, targeting the Phe43 cavity of gp120. NBD-11021 was found to bind to gp120 and block gp120-CD4 interaction, prevent cell-to-cell fusion and block cellassociated transmission of HIV-1. The molecule was also discovered to target HIV-1 transcriptase, the enzyme the virus employs to manufacture complementary DNA, though with lower potency. This could potentially be another mechanism of action
through which the molecule may be effective against HIV-1 infection. PAVING THE WAY FOR NOVEL THERAPEUTICS They are now working to further develop more potent entry inhibitors from NBD-11021, with a higher selectivity index for pre-clinical studies. Their pioneering research also paves the way for further development of other molecules in the NBD series for clinical application. Another project they are working on is attempting to discover the best combination of drugs known as latency reversing agents (LRAs), which will facilitate to eradicate HIV-1 from virus reservoirs. If an effective combination can be found to totally eradicate the virus from reservoirs by antibody drug conjugates (ADC) and the immune system, this will aid the development of a functional HIV-1 cure. They are also working on identifying new agents capable of inactivating pathogens in blood products. Dr Debnath hopes that his team’s contributions thus far, along with their future research, will pave the way for discovery of a new class of anti-HIV-1 drugs targeted at the gp120-CD4 binding site. Their novel approach to drug development has opened up several avenues for further research to develop such therapeutics, which are urgently needed to deliver new drugs.
COLLABORATORS • Dr Francesca Curreli, Assistant Member in Dr Debnath’s lab • Dr Peter Kwong, Chief, Structural Biology Section, Vaccine Research Center, NIAID, NIH • Dr Young Do Kwon, Vaccine Research Center, NIAID, NIH • Dr Andrea Altieri, Chemist, Edasa Scientific, Russia, and his team BIO Dr Asim K Debnath received his PhD in Medicinal Chemistry in 1987 from Jadavpur University, Kolkata, India and completed his postdoctoral study with Prof. Corwin Hansch at Pomona College, California, USA. He is a Member (equivalent to Professor) and Head of the Laboratory of Molecule Modeling & Drug Design at the Lindsley F Kimball Research Institute of the New York Blood Center. Dr Debnath has been active in antiviral drug design research for the last 20 years. Dr Debnath has published more than 97 peer-reviewed research papers and he has 14 US issued patents. CONTACT Asim K Debnath, PhD, Head, Laboratory of Molecular Modeling & Drug Design, Member, Lindsley F. Kimball Research Institute, New York Blood Center, 310 E 67th Street New York, NY 10065 E: ADebnath@nybc.org T: +1 (212) 570-3373 W: http://nybloodcenter.org/productsservices/kimball-research-institute/ asim-k-debnath-phd/
Promising protein research for neurodegenerative diseases Since the discovery that neurofibrillary tangles are a hallmark present in Alzheimerâ€™s disease, Professor Gloria Lee has been at the forefront of research investigating tau, the protein that is implicated in the formation of these structures. Her work has contributed to elucidating both targets for therapeutic intervention and biomarkers for early diagnostic testing.
Out of all the research you have worked on through your career on tau, what discovery was the most challenging to produce evidence for? Showing the association of endogenous tau with Fyn in neuronal cells was most challenging. This was almost 20 years ago – it was necessary to isolate a complex of tau and Fyn and finding the right conditions to break open the cells and to recover a lysate that contained the complex was time consuming. Looking back, it is likely that the complex was in lipid rafts (unknown at the time) and, for that reason, the use of detergent solubilisation was not straightforward. What do you think are the most promising avenues for therapeutic targets and intervention of the progression of Alzheimer’s disease? I do not believe that the plaques and tangles are the best therapeutic targets. I would rather target an early aspect of the disease, which would mean targeting Aβ oligomers or hyperphosphorylated tau or tau oligomers. I believe that Aβ oligomers are activating abnormal signalling pathways that create abnormal forms of tau, which then go on to cause neurodegeneration. Disrupting the signalling pathway can be achieved by eliminating abnormal Aβ or tau, or by identifying and eliminating other members of the activated pathways. How far are we from having early diagnostic testing available for Alzheimer’s disease, and how will this relate to your research on tau? The ability to image abnormal tau using PET is under development and such a tool would be useful as an early diagnostic test. Various probes are currently being tested. The availability of patients with documented early Alzheimer’s would be useful since we could then obtain plasma and other samples for use in testing. In particular, we would be interested to determine if tyrosine phosphorylated tau was an early marker in plasma. Tyrosine phosphorylation is characteristic of signalling events and adult tau is not normally tyrosine phosphorylated. When
we found that tau in Alzheimer’s acquired tyrosine phosphorylation, this suggested that tau had acquired new properties, possibly participating in abnormal signalling pathways. We speculate that this happens early in the neurodegenerative process. While the imaging test would definitely be useful, developing an easier and less expensive test for early Alzheimer’s would also be useful. What, in the context of your research, has been the most exciting technological advance that has occurred during your career and what impact did this have on your research? Many technological advances have occurred during my career and it is difficult to pick out the "most exciting" one. For instance, DNA sequencing was discovered when I was a graduate student and my thesis involved DNA and RNA sequencing. Among the many technological advances that have been made, we have extensively used “transfection” which is a technique where one can express an engineered protein (such as a tagged wild type, mutant, or fragment) in mammalian cells. Another advance was the ability to make monoclonal antibodies in mice. This allowed us to make an antibody that recognizes tau with phospho-tyrosine at a specific residue. Confocal microscopy is another advance that has been useful for us. The most recent, exciting technological advance that has aided our research is the development of the proximity ligation assay. This technique allows us to locate protein complexes in cells, using fluorescence microscopy. What are your hopes for future outcomes of your current research in the coming years? I hope to elucidate the function of the tau–Fyn interaction in the developing brain and in the neurodegenerative process. Given that Fyn is a tyrosine kinase, the interaction is likely to be involved in signalling. Knowing the function of tau–Fyn interaction in the neurodegenerative process would aid in identifying abnormal signalling pathways activated, thus giving us more targets for therapeutics and early diagnostics.
lzheimer's disease, named after Alois Alzheimer who first described the condition in 1906, is the most common cause of dementia, accounting for 60-70% of cases. The development of the disease is associated with the formation of structures in the brain known as tangles and plaques, which are accompanied by the death of neuronal cells and loss of brain tissue. Dr Gloria Lee, Professor of Internal Medicine at the University of Iowa, Carver College of Medicine, researches the protein tau and its involvement in Alzheimer’s disease. The protein is critical for neuronal development and is the primary component found in the neurofibrillary tangles associated with the disease. Mutations in the gene encoding tau have also been linked to other neurodegenerative diseases including frontotemporal dementia. Therefore, understanding the structure and function of tau is of great importance to biomedical research, with far reaching implications for the development of treatments for neurodegenerative conditions. EXISTING CHALLENGES Currently, there is no known cure for Alzheimer's disease, with no treatment available that can halt or reverse its progression. The disease is difficult to diagnose in the early stages, as the symptoms can be subtle, resemble other illnesses or appear similar to normal signs of ageing. As current methods of diagnosis are largely based on documenting clear signs of mental decline, by the time the disease is identified, severe brain damage will have already occurred. Therefore, it is essential that new ways of diagnosing the illness in its very early stages are found, in addition to targets for therapeutic intervention of the disease. When Professor Lee first embarked on her research investigating tau more than 30 years ago, the protein had not yet been linked to Alzheimer’s disease. Once the connection had been made, she says she, ’felt that tau would be important and understanding its uniqueness would give us some clues into its role in Alzheimer’s disease’. LAYING THE FOUNDATIONS Her early research was focused on first elucidating the basic aspects of the protein itself, with her work being the first to describe the DNA sequence that encodes it. Armed with this knowledge, she delved further into studying the function of the protein. Lee felt
Degenerating neurones in an Alzheimer’s disease brain section labelled with an antibody developed against tyrosine phosphorylated tau.
Understanding the structure and function of tau is of great importance to biomedical research, with far reaching implications for the development of treatments for neurodegenerative conditions that detailed structure and function studies of tau were essential in order to understand the microtubule binding properties of the protein, with the hope of providing the best chance of finding targets for therapeutic intervention. Lee and her team identified a region of the protein that is comprised of repeats in the sequence that they demonstrated as having the ability to bind to structural components in cells, known as microtubules. Microtubules are vital cellular components integral to the cell cytoskeleton, which, as well as providing structural support to the cell, are involved in many dynamic cellular processes such as intracellular transport, mitosis and cell migration. The distribution of microtubules varies between cell type and the highest concentration is found in cells in the brain, with tau proteins responsible for stabilising microtubules and promoting their growth. Lee and her research group identified the region of tau that is involved in binding the protein to microtubules and upon further investigating this region, they discovered that a specific part of this region is required to "nucleate" the formation of new microtubules, in addition to promoting the growth of existing ones. Other researchers used this knowledge to further investigate how the region is fundamental to microtubule binding. In Alzheimer’s, the loss of tau’s ability to stabilize microtubules has been thought to be critical to the neurodegenerative process. Therefore, understanding the molecular level through which tau acts is useful for developing agents to compensate for the loss of tau. EXPANDING THE RESEARCH Lee’s research also led her to work on the first ever project to look at neurofibrillary tangles in an animal model using lamprey, a type of fish commonly used in biomedical studies. Together with Dr Garth Hall, they showed that genetically modifying the lampreys’ cells to produce excessive quantities of human tau protein resulted in the tangle-like structures. This discovery spurred on other researchers to develop a mammalian system in which neurofibrillary tangles could be observed.
Professor Lee’s group also investigated what other roles tau plays in cells, in isolation of microtubules. Lee explains that she chose to focus on one of the end regions of the protein as it was unique and the function of the domain was unknown. This led to the finding that tau can associate with the plasma membrane of cells, which occurs independently to what had been found regarding its microtubule binding ability. The plasma membrane of cells is a site of signal transduction for cells, where signals are received from sources outside the cell, interacting with proteins on the plasma membrane, which go on to influence events inside the cell. IDENTIFYING A KEY EARLY PROCESS Given tau’s association with the plasma membrane, they have discovered that tau is also involved in cell signalling and identified several previously unknown interacting proteins. One of these interacting partners is known as Fyn, a tyrosine kinase, and they found that tau was phosphorylated on tyrosine as a result of this interaction. In addition, they found that mutant forms of tau, linked to other neurodegenerative diseases such as frontotemporal dementia, had increased association with Fyn. Her team also developed an antibody that recognises the phosphorylated form of tau created by Fyn. They have utilised this new antibody in their research to show that this modification occurs in both the developing brain and in cases of Alzheimer’s. The antibody is now commercially available for research purposes and negotiations are in process regarding its use for immunotherapy. Lee and her team continue to investigate the role that tau plays in the pathology of Alzheimer’s. Currently they are investigating the role of tau in cell signalling during neuronal differentiation, hoping to reveal the mechanism by which this occurs. They are also continuing to delve deeper into the details of the interaction between Fyn and tau, hoping that their work will yield even more avenues for research into therapeutic intervention for neurodegenerative diseases.
Detail RESEARCH OBJECTIVES Dr Lee’s research focuses on the tau protein and its role in the development of Alzheimer’s disease. Over 30 years of work she has helped to elucidate its structure and function as well as its role in neurodegeneration. COLLABORATORS • Roland Brandt, Professor in Germany • K iran Bhaskar, Assistant Professor in New Mexico • G arth Hall, Associate Professor in Massachusetts BIO After receiving her PhD from Harvard University, Dr Lee completed her post-doc work at the University of California. When she started to work on tau in Marc Kirschner’s lab, the connection to Alzheimer’s disease had not yet been made. When the connection was made, she was offered a job in Neurology at Harvard Medical School, despite having no background in neurology or human disease. She continued to work on tau, certain that it would be important and that understanding its uniqueness would give some clues into its role in Alzheimer’s. Dr Lee moved to the University of Iowa in 1998, the same year that mutations in tau were found to cause frontotemporal dementia. She has continued to work on tau and her research has influenced others in the field. CONTACT Gloria Lee, PhD Professor Department of Internal Medicine University of Iowa College of Medicine ML B191 Iowa City, IA 52242 USA E: email@example.com T: +1 319 335 9223 W: http://molcellbio.grad.uiowa.edu/ faculty/Gloria-Lee
Miracle berries: how blueberries can improve bone health Connie Weaver, PhD, is Distinguished Professor and Head of the Department of Nutrition Science, Director of the WGHI (Women’s Global Health Institute), and Deputy Director of the Indiana CTSI (Clinical and Translational Sciences Institue) at Purdue University. As part of the collaborative ‘Berries and Bone’ project, she has been investigating whether blueberries may be an appropriate dietary alternative to conventional medicines that prevent bone loss in post-menopausal women.
What was your primary motivation for the ‘Berries and Bone’ project? I am an expert in mineral metabolism, bioavailability, and function. Early in my career, I studied the trace minerals iron, zinc, and selenium. After 1990, I focused on calcium. Over 99% of calcium in the body is in bone and it is the dominant mineral in bone mineral. I began studies to determine optimal calcium intakes for building peak bone mass in girls and boys of different race and ethnicity. That work led to the recommendations for calcium intake in adolescents in North America. Building peak bone mass is an important strategy to preventing fracture while young, but even more important later in life. Almost 80% of fractures occur in women, so osteoporosis has largely been considered a women’s disease. Working in this area of chronic disease for three decades made me sensitive to the under-study of women’s chronic diseases generally. So, I started a Global Women’s Health Institute at Purdue in 2012 to stimulate research and training in women’s diseases, especially osteoporosis, women’s cancers, neurodegeneration, and wellness using the high science and engineering strengths of Purdue. I am interested in many bioactive sources and functional foods. I have had the most success getting funding for blueberries to lower risk of osteoporosis to date. I am also pursuing work with plums. Until we know the bioactive compounds in each and their mechanism of action, we will not know if several fruits can be interchangeable in health benefits or if there are advantages to one over the other. And it isn’t as simple as blueberries as a whole. With 1200 different varieties of blueberries, I expect that some will have greater health benefits than others. Did you find there were benefits to working in such an interdisciplinary team? Always. In trying to solve the complex problems of today, interdisciplinary research teams are imperative. My collaborators can bring different perspectives as well as a different knowledge base. As a scientist, networking allows you to reach out to others working in related fields and it also helps build
long-term working relationships that really benefit your work. Could your results be useful in treating bone-related conditions in men as well as women? This is an interesting avenue for us to explore. Our animal studies show sex differences in the skeleton so we will be evaluating sex differences in response to feeding blueberries in mice. Men do not have the rapid loss of bone that women have with the menopause. Bone loss in men is associated with a more gradual loss of oestrogen as with women more than five years postmenopausal. Thus, we have thought that osteoporosis in men occurs at a more advanced age than in women. Recent statistics show that life expectancy in men is increasing at a faster rate than in women so we need to consider bone health for men more seriously. Would including polyphenol-rich foods in one’s diet from a younger (pre-menopausal) age make preventing age-related bone loss even more effective? Animal studies show that they are effective in multiple life stages. Generally, it is thought that building higher peak bone mass during growth has the greatest ability to reduce fracture later in life. Bone mass is more stable from about 30 years old to menopause. In animal models, blueberries have been shown to reduce the rapid bone loss with the loss of oestrogen at menopause so this would be a particularly good time to eat plenty of berries and plums. Polyphenol-rich fruits also increase bone formation after the rapid loss of bone with menopause, but this is never as effective as preventing the bone loss in the first place. What sort of quantities of blueberries do you expect would be beneficial to health? Unfortunately, we don’t know this exactly. We are planning to test this in the future so that we are able to give some specific advice about how many blueberries to eat to prevent age-related bone loss. There is a practical limit to how many blueberries can feasibly be incorporated into the diet. We hope that benefits occur at achievable doses for the general population.
lthough not usually life threatening, the number of bone fractures experienced by people in the US exceeds those of cancer, heart attacks and strokes combined. Fractures are more likely in those who have weaker bones as a result of conditions like osteoporosis, which can be treated but currently has no cure. Following the menopause or an ovariectomy (removal of the ovaries), the amount of oestrogen in a woman’s body dramatically reduces. This causes the accumulation of reactive oxygen species (ROS) in the body, which, as the name suggests, are highly reactive, and can cause deterioration of the bones. Previous treatments have included oestrogen therapy (also known as HRT), but this has been shown to incur adverse side effects. The team at Purdue has been trying to identify alternative ways of preventing bone loss in women after this drop-off in oestrogen levels, that do not involve having to take medication. Weaver’s hypothesis is that blueberries can help the immune system defend against bone loss. To test this, the team selected several blueberry strains, trying to choose varieties that were as different from each other as possible, to find out whether the different chemical properties of these berries had an effect on the clinical outcome. So far, they have had some promising results from animal models and hope to find the most effective variety of blueberry for the prevention of bone loss in humans. WHAT’S SO SPECIAL ABOUT BLUEBERRIES? Blueberries contain bioactive compounds called polyphenols. According to the US National Institutes of Health, ’bioactive compounds are constituents in foods or dietary supplements, other than those needed to meet basic human nutritional needs, which are responsible for changes in health status’. Polyphenolic compounds are known to reduce bone loss by helping to modulate cell-signalling pathways that cause oxidative stress and inflammation, both factors that affect bone formation and loss. IT’S THE TRANSCRIPTION THAT COUNTS Nrf2 is a protein called a transcription factor, that binds to select sections of genetic code and controls the rate of transcription of specific sequences of information. This means that Nrf2 can stimulate the expression of certain genes that can detoxify ROS.
Following the sharp reduction in oestrogen formation that occurs post-menopause, inflammatory processes become more active, and this causes an increase in bone resorption. This is a process whereby cells called osteoclasts break down bone and release the constituent parts, such as calcium, into the blood. Nrf2 plays a role in controlling inflammation, but the exact mechanisms by which it works, and the way in which it is modulated by blueberry phenolic compounds, are unknown. However, its role in detoxifying ROS has been quantified: Nrf2 binds to antioxidant response elements (AREs), which stimulate the transcription of antioxidant enzymes that protect against the damaging effects of ROS. Phenolic compounds also inhibit the transcription factor NFκB, which stimulates the expression of genes that prevent bone formation. NFκB increases the activity of osteoclasts, which break down and resorb bone material, and suppresses the activity of osteoblasts, which are responsible for bone formation. Therefore, suppressing NFκB causes osteoblasts to form more new bone material and retain calcium better, while the activity of osteoclasts is reduced. GUT FEELING Microbiota in the gut are also likely implicated in the phenol-induced reduction in bone loss. Oestrogen deficiency changes the make-up of microbiotic communities in the gut, which are essential for health. Those with higher gut microbiotic diversity generally have lower rates of inflammation. Gut inflammation is linked to bone loss, and of course the loss of oestrogen causes the accumulation of ROS, and increases inflammation. The benefits of phenolic compounds are not merely incurred by the products themselves. They also arise as a result of the interaction between polyphenols and gut microflora. Bacteria facilitate the uptake and metabolism of phenolic compounds. These interactions and processes in the gut are an important
part of the health outcomes that bioactive compounds like polyphenols provide. AN INTERDISCIPLINARY APPROACH The ‘Berries and Bone’ project, funded by the NIH National Center for Complimentary and Integrative Health, involves numerous different approaches and facets, and the testing of their hypothesis employs many different techniques and disciplines, including a clinical trial, isotopic tracer
Weaver’s work suggests that prevention of some diseases, such as osteoporosis in older women, is achievable with dietary measures www.researchfeatures.com
Detail RESEARCH OBJECTIVES Professor Connie Weaver and her team are studying the most effective blueberry line for improving bone density and strength and preventing bone loss in postmenopausal women and animal models. Understanding the mechanism by which berries ameliorate menopause-induced and age-related bone loss is one of the most compelling avenues to pursue in natural products research. COLLABORATORS • George McCabe, Purdue University • Teresito Bellido, Indiana University School of Medicine • David Burr, Indiana University School of Medicine • Munro Peacock, Indiana University School of Medicine • Mario Ferruzzi, North Carolina State University • Mary Ann Lila, North Carolina State University BIO Connie M Weaver, PhD, is Distinguished Professor and Head, Department of Nutrition Science; Director, WGHI; and Deputy Director, Indiana CTSI at Purdue University. She is a member of the following: NAM, FDA Science Advisory Board, NIH ACRWH, and Vice Chair of the Board of Trustees, ILSI. analysis, bioactive activity analysis, epigenetics, cell culture and animal studies, nutrition and statistical analysis. As a result, Weaver collaborates with researchers at various institutions, such as Teresito Bellido, David Burr and Munro Peacock at the Indiana University School of Medicine, Mario Ferruzzi and Mary Ann Lila at North Carolina State University, as well as George McCabe, her colleague at Purdue. CAN DIET REPLACE TREATMENT AS A PRIMARY PREVENTION FOR CHRONIC DISEASE? The Purdue team has shown that administration of natural antioxidant-rich products, such as blueberries, reduced bone loss in mice. They now need to translate these findings into the effects on humans. They have used animal models to
find a dosage that can stimulate a positive effect, and will apply these findings to upcoming clinical trials following their approval. Weaver’s work suggests that prevention of some diseases, such as osteoporosis in older women, is achievable with dietary measures. As the adage goes, prevention is better than cure – both in terms of patient health outcomes, and the financial burden on healthcare services. Purdue is at the forefront of the drive to understand how berries can benefit bone formation. Encouraging patients to include phenolic berries in their diets could greatly lower their risk of developing problems related to bone loss or low bone mass, and could be an attractive alternative to conventional medicine-based treatment.
CONTACT Connie M Weaver, PhD Distinguished Professor and Department Head Director, Women's Global Health Institute Purdue University, Nutrition Science 700 W State Street West Lafayette, IN 47907-2059 E: firstname.lastname@example.org T: +1 765 494 8237 W: https://www.purdue.edu/hhs/nutr/ directory/faculty/weaver_connie.html
UK Biobank Unlocking the statistics of ill health Professor Sir Rory Collins discusses his role as Principal Investigator and Chief Executive of UK Biobank, a major future-focused national health resource and registered charity that aims to improve the prevention, diagnosis and treatment of a wide range of serious and life-threatening illnesses.
K Biobank is leading the way by developing a powerful resource for researchers to help improve our future health. Recruiting half a million people aged 40–69 during 2006 to 2010 for a large cohort study, UK Biobank is collecting vital data to increase knowledge about a wide range of serious illnesses, such as cancer, heart diseases, stroke, diabetes, arthritis, osteoporosis, eye disorders, and depression, as well as forms of dementia. The 500,000 participants had physical measures made and answered detailed questions about themselves. UK Biobank also collected samples of the subjects’ blood, urine, and saliva for future analysis and are now tracking the participants’ health over time through medical record systems. Moving forward as the study continues, UK Biobank is building this powerful resource to allow other scientists from around the world to use it to discover why some people develop particular diseases and others do not.
What is your role as the Principal Investigator and CEO of UK Biobank? The aim of UK Biobank is to establish a large prospective cohort that allows researchers from around the world to find out more about the causes of many different diseases. In order for the resource to be as useful as possible for researchers, we first had to recruit a large number of participants; between 2006 and 2010, 500,000 people aged 40–69 joined the project. We then had to find out as much as we could about them – that involved asking them lots of questions about their lifestyle, environment, and health, and making lots of measurements of the participants (including things like blood pressure); as well as collecting blood, urine and saliva for future assays. Finally, we then have to find out about all of the many health conditions that the participants develop subsequently. This involves UK Biobank linking (with consent) with different electronic health record systems, to find out about deaths, cancers, hospitalisations, and GP care among the participants. My role is to coordinate the team responsible for building this resource, making it more useful for researchers, such as generating genotype and other assay data available from all the participants, and turning health record data into specific information about particular health outcomes. My role also includes encouraging and facilitating use of the resource by researchers, so that UK Biobank generates lots of novel findings that help to improve human health. Could you tell us about some of UK Biobank’s key current projects? As the team responsible for building the UK Biobank resource, our recent focus has been on enhancing its value for research. For example, we have been using webbased questionnaires to find out more about the participants’ diet and work history as potential “exposures” that could impact on the development of particular conditions. Similarly, we have been measuring the amount and intensity of their activity by getting them to wear accelerometers. With regards to finding out about diseases that participants develop during follow-up, our focus has been on getting access to all of the different health record systems that can provide such information. We then have to use the data from these different systems (which are not necessarily accurate or complete) to determine whether the participant really has had a health outcome,
UK Biobank is ALL about the long-term. It has involved the funders – UK government’s Medical Research Council and Wellcome Trust UK charity – to take a long-term perspective such as a stroke or breast cancer. We also need to ascertain the particular type, for example if the health outcome is a stroke due to a blood clot or a bleed, or breast cancer with or without hormone receptors. We need to determine these details because exposures may be specifically related to a particular type of disease – for instance, something that makes blood less likely to clot may result in lower risk of strokes that are caused by clots, but higher risks of strokes due to bleeds. By characterising the participants’ exposures and their diseases very specifically, we will make the resource much more useful for researchers to find out about specific causes of disease. UK Biobank recently launched the world’s biggest body-scanning project. How do you hope this will shed new light on major diseases? The largest previous imaging studies that have been conducted involved less than 10,000 individuals (typically far fewer) and tended to focus on one part of the body (e.g. the heart or the brain). By contrast, 100,000 of UK Biobank’s participants will have Magnetic Resonance Imaging (MRI) of their brain, heart and body, and low-power DEXA X-ray of their body, bones and joints, as well as an ultrasound of the arteries in their neck. Researchers will be able to combine this imaging data with all of the other information that we have collected about the participants’ previous exposures, including genotype and assay data, and their subsequent health conditions. This uniquely detailed largescale resource should allow very many novel findings to emerge. As one obvious example, body mass index (BMI) derived from weight and height is known to be strongly associated with the risk of having a heart attack or a stroke. However, we also know that BMI does not provide a good assessment of the amount or distribution of fat in the body. For example, someone with a lot of muscle, but little fat, will have a high BMI. Also, people with the same BMI may have very different amounts of fat around their body organs, or so-called “visceral” fat, which
is thought to be more relevant to obesityrelated conditions. By contrast, body MRI provides very specific information about fat amount and distribution; so the assessment of such large numbers of people will allow researchers to assess the relevance of fat to disease far more specifically than has ever previously been possible. Likewise, detailed brain imaging (which provides information not only about structure but also about function) may well – when combined with information on cognitive function and genotype – allow causes of dementia to be identified. What impact do you think UK Biobank has made to date for improving the prevention, diagnosis and treatment of serious and lifethreatening illnesses? UK Biobank has been designed as a “prospective” cohort. By using this term, I mean that UK Biobank involves first assessing “exposures” at the start in very large numbers of participants, then looking to see whether there are differences between the exposures of participants who develop a particular condition subsequently during follow-up, and those who do not develop the particular condition. This approach allows researchers to identify novel causes of different diseases. However, UK Biobank’s approach requires not only the assessment of very large numbers of people, but also sufficient duration of follow-up, in order for large enough numbers of participants to have developed any particular condition. The participants in UK Biobank had their baseline assessment of exposures conducted in 2006–2010, so they are only now starting to have had enough follow-up for there to be large enough numbers of some of the more common conditions (such as heart attacks and certain types of cancer). Consequently, although many researchers from around the world have already started to use the resource, and an increasing number of reports on their results are being published, my view is that it will only be in the next 5-10 years that the promise of UK Biobank will be realised.
Does UK Biobank have any exciting new projects in the pipeline? Having been able to get additional funding to genotype all of the participants in UK Biobank, as well as to measure biochemical markers in their blood and urine samples (such as cholesterol levels), it has become clear that this is a particularly effective way to increase the accessibility of the resource to researchers. That is to say, rather than require individual researchers to find funding for assays, UK Biobank obtains funding to conduct assays that can be widely used by many different researchers. As a result, we are now seeking additional funding to conduct further sets of assays – for example, looking for markers of exposure to infectious agents, which may be related to risks of cancer and cardiovascular disease. We are also working with researchers who would like to conduct prolonged assessment of cardiac rhythm disturbances (because many “arrhythmias” come and go, they are not detected by a single ECG recording) using a novel device, which can be worn without interfering with normal activities (as we did previously for physical activity). It seems likely that new technology will allow us in the future to assess an increasing range of different exposures among participants. How would you describe UK Biobank’s long term strategy? UK Biobank is ALL about the long-term. It has involved the funders – UK government’s Medical Research Council and Wellcome Trust UK charity – to take a long-term perspective. They have invested substantial amounts of research funding (about $200M so far), with the expectation of little return in terms of life-changing research findings during the first 15 years of the project. Our job now is to make sure that researchers take advantage of the funders’ vision, and turn that investment into new knowledge that in turn helps to reduce death, disability and misery caused by many different conditions. In 2011 you were knighted by the Queen for your services to science. What did it mean for you to have recognition of your fantastic achievements in the areas of heart attacks, other vascular disease, and cancer? The reality was that my knighthood was recognition of the work of all of the UK Biobank team. On a personal note though, it was particularly special that my mother was able to attend the ceremony and see that her long-term “investment” in me (like that of the funders of UK Biobank) had paid off!
What would you personally like to see happen in the future at UK Biobank? UK Biobank has been established to be a resource for academic and commercial researchers to use, without preferential or exclusive access, for any type of health-related research that is in the public interest. My hope is that in the next 5–10 years we will see an increasing number and range of findings emerge from UK Biobank, from many different researchers based all around the world, about the causes of many different diseases and of ways to prevent and treat them. • Rory Collins became co-director of Oxford University’s Clinical Trial Service Unit in 1985, BHF Professor of Medicine & Epidemiology in 1996, and UK Biobank Principal Investigator in 2005. His work has been in establishing large-scale epidemiological studies of causes, prevention and treatment of heart attacks, other vascular disease, and cancer.
Contact UK Biobank 1-2 Spectrum Way, Adswood Stockport SK3 0SA W: www.ukbiobank.ac.uk T: +44 (0)800 0 276 276 E: email@example.com @uk_biobank UK Biobank UK Biobank
Melanin-regulating ion channels discovery A new study by Dr Elena Oancea and her laboratory at Brown University reveals the mechanism that regulates pigmentation. The discovery could aid development of future treatments for skin, eye and hair disorders caused by defective melanin production.
Ion channels that regulate melanin were discovered using patch clamp recordings of melanosomes, the cellular organelles that produce and store melanin. A glass patch pipette (shown in blue) was used to cut a small slit into the plasma membrane of a skin melanocyte in order to expose and patch a melanosome (small circle filled with blue) that is 1-3 microns in size.
What are the implications of your new understanding of ionic signalling in melanosomes? Beginning to understand ionic signalling in melanosomes is an important step towards understanding the complex mechanisms that regulate pigment generation and storage in the eye, skin and hair. Because melanosomes are the best-studied model for lysosomal-related organelles, understanding melanosome function will be highly relevant for other organelles, such as platelet dense granules and lung alveolar type II lamellar bodies.
How did it feel to answer some of the key questions that arose from your previous research? The TPC2 study was developed almost in parallel with the first OCA2 study that we published. Once we were able to measure ionic fluxes across melanosomal membranes, we found the anionic conductance mediated by OCA2 and the cationic one mediated by TPC2. There are certainly many more ion channels and/or transporters in melanosomes, but these were the first two that we could measure under our experimental conditions.
Could you speculate what new treatments for pigmentation disorders and skin cancers may arise from your research? It is too early to think about treatments, as we are only starting to understand how these molecules work. If I were to speculate based on our data, at least for some forms of albinism, decreasing melanosomal acidity could restore pigmentation levels. Altering melanosomal pH, however, without changing the acidity of other cellular organelles (like lysosomes or endosomes) is not a trivial task. We discovered that TPC2 is a negative regulator for pigmentation and thus blocking its ion channel activity could lead to more pigment being produced. This would also be very difficult, as TPC2 functions in the lysosomes of most cells in our body and is important for their function.
What direction do you think your future research will take? We would first like to understand how the currents mediated by these two channels are regulated by different cellular signals, from the cytosolic side or from the melanosomal lumen side. In other words, are these channels always open or are there specific molecules that, when produced or activated in the cell, bind to the channels and allow them to open? We would also like to get a more complete picture of melanosomal physiology: What other channels are present in melanosomes and how do they function? How do the proteins encoded by genes mutated in other forms of oculocutaneous albinism contribute to pigmentation? What allows proteins like TPC2 to function only in melanosomes in melanocytes and in lysosomes in all the other cells?
elanin is our bodyâ€™s natural pigment, responsible for the colour of our hair, eyes and skin. Skin disorders such as albinism, vitiligo and hyperpigmentation, occur when our cells abnormally synthesise or over/under produce melanin. As in the commonly known albino symptoms of pale skin, eyes and hair, the underproduction of melanin
affects the development and function of the visual system and reduces an individualâ€™s protection against ultraviolet radiation. Worryingly, individuals who underproduce melanin are at increased risk of skin and eye cancers as their DNA is more exposed to harmful ultraviolet radiation. On the opposite side of the spectrum, the overproduction of melanin is usually a benign condition, with many choosing to embrace their unique
hyperpigmentation. However, in some cases, the appearance of blotchy, asymmetrical dark patches can have a negative psychological impact. To avoid defective melanin synthesis, a delicate balance of pigment production is required. FINDING THE BALANCE Melanosomes are specialised organelles within skin melanocytes and ocular pigment cells that regulate the production and storage of melanin. Melanosomes are surrounded by a membrane that contains transmembrane proteins that regulate the flux of ions into or out of the melanosomes, a process critical for pigment production in these organelles. Dr Elena Oancea and her team at Brown University, have been studying ionic signalling in melanosomes, or how exactly ion channels regulate melanin synthesis, storage, and transfer. In 2014, the team made their first breakthrough, identifying an ion channel called OCA2 that is defective in people with oculocutaneous albinism type 2 (OCA2) and that functions to increase the production of melanin. More recently, the team found the counterpart to OCA2 - an ion channel with the reverse effect on cellular pigment production. In their new study, Dr Oanceaâ€™s team have discovered a new regulatory protein for the pigmentation process: two-pore channel 2 (TPC2). The team had a clue that TPC2 relates to pigmentation as two mutations in the gene encoding the ion channel were linked to light hair colour and fair skin in a 2008 study of northern Europeans. Using direct patchclamp recordings, a laboratory technique that allows the study of ion channels, of skin and eye melanosomes from mouse melanocytes and frog retinal pigment cells, the researchers were able to identify the first reported melanosomal cation conductance mediated by TPC2. Mouse skin cells and frog eye cells have the same proteins and mechanisms as in humans. However, the melanosomes are larger making the experiments possible. In the laboratory, Dr Oancea and the colead authors Nicholas Bellono and Illiana Escobar, measured the flux of ions across the membranes that surround the melanosomes found inside melanocytes. They found an electrical current that corresponds to positive ions flowing out of the organelles, into the cytoplasm. Notably, this current was found to be independent of the already known OCA2 ion channel, which the same group showed transports negative ions
out of the melanosomes. The new current was consistent with a typical two-pore channel and appeared to depend on a lipid (fat) named PI(3,5)P2 that exists in the membrane around the melanosome and other cellular organelles. Investigating further, the researchers added verapamil to the cell culture, a chemical that blocks the activity
of both TPC channels. This stopped the electrical current, as they had expected, and further experiments identified that the ion channels are of the TPC2 variety, not TPC1. The team deleted the TPC2 gene using a gene editing tool called CRISPR-Cas9, confirming that the outflow of positive charges
Defective Melanin Synthesis Disorder
Underproduction and storage of melanin
Overproduction and storage of melanin
Affects 1 in 17,000 people worldwide
Global prevalence unknown relatively understudied area of dermatology
Male and females equally affected, except for sub-type ocular albinism that occurs more often in males
Between 75-90% affected are female
Can affect individuals of all ethnicities
More common in people with naturally darker skin, or who tan easily
Very pale skin, eyes and hair
Symmetrical, blotchy, brownish facial pigmentation
Causes problems with eyesight
Benign condition, but can cause significant psychological distress and embarrassment
Increased risk of skin and eye cancers
Providing vital knowledge required to construct a comprehensive model of ionic signalling in melanosomes, the researchers have provided a significant step towards a better understanding of human pigmentation
from melanosomes is indeed mediated by the TPC2 ion channel. What’s more, they could reestablish the flow of current by adding the TPC2 gene back into the cells. During this process, they observed that the melanosomes of cells with fewer TPC2 channels are less acidic and produce more melanin, suggesting TPC2 is a negative regulator of pigmentation. They discovered that TPC2 counterbalances OCA2, a positive regulator of pigmentation, by increasing the melanosomal membrane potential and acidity to decrease melanin content. In simple terms, if TCP2 lets too many positive ions escape the melanosome, the production of melanin is turned off. PROGRESS FOR PIGMENT TREATMENT “We now know how TPC2 functions in melanosomes and can use this information to understand how melanosomes function under normal conditions, and how their function can be perturbed by mutations,” says Dr Oancea. Providing vital knowledge required to construct a comprehensive model of ionic signalling in melanosomes, the researchers have provided a significant step towards a better understanding of human pigmentation. The research team are hopeful that their
research will provide other scientists with the basis for uncovering “novel therapeutic targets” for pigmentation disorders, as well as skin and eye cancers. Perhaps as a result of the study, future research will be able to find a way to treat albinism and hyperpigmentation. Should that prediction prove correct, a significant proportion of skin and eye cancer could be pro-actively prevented, and much psychological distress eliminated. However, there is much research still to do, particularly due to the existence of TPC2 channels in other cells. Dr Oancea explains: “Unfortunately, this is not simple. TPC2 channels also have important functions in the lysosomes of non-pigment cells. Blocking TPC2 would not only increase pigmentation, but interfere with other functions mediated by the ion channels. Local delivery of specific TPC2 blockers to melanocytes might be a way to circumvent this problem.”
Detail RESEARCH OBJECTIVES The focus of Dr. Oancea’s laboratory is understanding signal transduction events primarily in pigment cells. Her research team investigates the molecular mechanisms mediating pigmentation in skin melanocytes and retinal pigmented epithelium, as well as the physiological and pathological effects of ultraviolet radiation on human skin. FUNDING National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) branch of the National Institutes of Health (NIH) COLLABORATORS Nick Bellono was a PhD student in Dr Oancea's laboratory, who did all the patchclamp recordings from melanosomes after learning how to patch lysosomes in Dr Dejian Ren’s laboratory at University of Pennsylvania. Bellono then adapted the technique to melanosomes. A key collaborator on the OCA2 paper, adviser, and friend of Dr Oancea is Dr Michael Marks from University of Pennsylvania. BIO Associate Professor Elena Oancea earned her PhD at Duke University with Dr Tobias Meyer then worked with Dr David Clapham at Harvard University / Boston Children’s Hospital. In 2008 Dr Oancea moved to Brown University to start her own lab and also shifted the focus of her research to pigment cells, how these cells respond to different physiological stimuli and the complex mechanisms that govern pigment production in melanosomes. CONTACT Department of Molecular Pharmacology, Physiology and Biotechnology Brown University Box G-B3 Providence, RI 02912, USA E: Elena_Oancea@brown.edu T: +1 401 863-6116 W: vivo.brown.edu/display/eoancea ElenaOancea
• Find out more about Dr Oancea’s research: www.nature.com/articles/srep26570 elifesciences.org/interviews/early-careerresearchers/elena-oancea
WHO WE ARE ADD International supports disability activists in Asia and Africa fighting for independence, equality and opportunity for disabled people. Disabled people living in poverty are among the most vulnerable and marginalised people on earth. Often, they have no access to basic human rights, education, or the opportunity to earn a living. That’s why all our work is driven by disability activists and their organisations. They have the passion and courage to fight for change. It’s their lives, and their communities, at stake. What they often need are the practical skills and resources to run an organisation. That’s where ADD International steps in.
We take the vision of disability activists and we give them the practical tools to turn that vision into functioning, powerful organisations. We call this process capacity building. It has transformed lives and built powerful movements for change. Tim Wainwright, ADD International Chief Executive: “We are not representatives of disabled people from developing countries. We are an ally to that group of people. It’s very dangerous to ever say that we understand what those groups want. Our role is to enable them to articulate what they want and to help them achieve it.”
“If you really want change to be embedded, yes you can give guidance, yes you can accompany people, but if you keep doing things for people, then it can be counterproductive, it can be disempowering. Once you’ve done something for yourself once, you can do it again.” “Capacity building disability activists and their organisations is an incredibly cost effective way of working. You’re not handing out services, you’re not handing out food or medical care. You are helping to figure out ways to ensure that disabled people have all those things as rights, not handouts.”
OUR WORK IN ACTION. SABINA’S STORY. Sabina was 6 months old when she got polio. In her rural community in Bangladesh, there were no health clinics to provide a vaccination. The polio left her physically disabled. As she grew up her neighbours told her she’d been cursed that she was paying for an ancestor’s wrongdoing. Their words were thick and constant, and with no alternative narrative to explain her impairment, Sabina started to believe them. She questioned what sins her grandparents must have committed. She shut herself away and withdrew deeper and deeper into herself. One by one she relinquished every dream she had for her life. Then one day disability activists visited her village. They told Sabina that there were other disabled people, just like her. That she was entitled to the same rights as her neighbours. They persuaded Sabina to leave her home and meet with them. For the first time Sabina realised she wasn’t alone. Sabina is now an awardwinning women’s activist, transforming lives throughout her community. She is part of a network of thousands of disability activists working in extreme poverty to build movements for change. And we are with them every step of the way. “Women are like the broom in the house. The cheapest household appliance. The disabled woman is first a disabled person and then a woman. This is a vicious combination.
I always kept myself in a shell. People have dreams when they meet other people. When one lives within him or herself then there is very little chance of having a dream. I used to be reclusive and hide myself away. The question of my rights was a far cry. Through ADD I got capacity building training to build my confidence and skills. I am now the President of the district Women’s Council. Last year, the Ministry of Women’s Affairs awarded me a prize for my work. If we hear that a woman has been attacked we visit her and take the necessary action. Recently a disabled woman was raped. The villagers tried to cover it up. The girl was forced out of her home. I took the girl in and we worked hard to settle the case. We filed a report against the perpetrator. Before our group, disabled people weren’t allowed in the police station. We were driven out from the station gates. Now they give us chairs to sit on. When we see one disabled woman is in danger we feel that we ourselves are in danger. I take it like this: it could also happen to me. If we do not act to solve our problems then the negative propaganda in our society about the disabled women will remain intact. I dream of a society where there will be no word like ‘disabled’. All our work and endeavour will be successful when disabled people have the identity of a human being.”
We currently work in Bangladesh, Cambodia, Uganda, Sudan and Tanzania. In each county we support a network of disability activists to deliver life-changing work on the ground, and we help them lobby global leaders and people with the power to make real change. Our disability activists follow thematic work based around ending violence against disabled women and girls, inclusive education, economic opportunity, tackling the mental health crisis, water and sanitation access, or supporting people with albinism. One third of our funding comes through public support, the remaining two thirds is institutional support, provided by trusts and government.
Research is a critical part of our work to support the global case for disability inclusion. We are involved in several research projects and always advocate a participatory approach where disabled people are actively involved, often as the researchers themselves. Research areas either completed, or in the pipeline, include: • Reviewing implementation of the UN’s Convention on the Rights of Persons with Disabilities in Uganda • How far market-based approaches can reach very marginalised groups – particularly disabled people • The experiences of disabled children in Tanzania, through their own voices • Participatory research looking at issues of the carers of children with intellectual disabilities
We are keen to collaborate on research that relates to the achievement of the Sustainable Development Goals for disabled people e.g. How can we best facilitate disabled people’s participation in decision making on sustainable development? What are the costs (human and economic) if disabled people are excluded? And how can we best reach those who are very furthest behind, for example because of intersecting exclusion due to disability, gender, and ethnic identity? To start a conversation please contact info@ add.org.uk
Break Time App
CREATING MOVEMENT FOR A HEALTHIER LIFESTYLE
Sitting down at work all day, itching around in your seat just to try and get comfortable? Well it’s time to get rid of that numb bum and take a break. Long bouts of physical inactivity are well known no-noes for health. Research has shown that sitting down for longer than six hours per day is not only bad for brain function and muscle depletion, but it can also have detrimental effects on the body’s ability to break down fats and pump blood efficiently. This can result in weight gain, a reduced life expectancy and an increased risk of heart disease and type 2 diabetes. In other words, your job is slowly killing you. But no worries, you can always do exercise after work to make up for it, right? Well, research actually suggests that exercise does very little to combat the effects of sitting down for too long – in a similar way to the almost irreversible effect smoking has on the lungs. In fact, the best solution to prolonged periods of physical inactivity comes via taking breaks on a consistent basis throughout the day, breaking up the length of time you are sitting down for – and this is where Break Time comes in.
Break Time is a free app designed to get you up and moving. Using a timespan of between 25 and 60 minutes that you can set yourself, Break Time will notify you to take a break and move around the office. This notification can be personalised and the activity you choose to do during your break is completely up to you: the app offers a choice between a simple buzz notification, a short workout, a quick dance to your own music, a set of yoga exercises or a mix of specific eye exercises. You can also set the app to open a website of your own choosing. Taking only a five-minute break every hour is enough to combat the negative effects of physical inactivity. Break Time makes this process easier, by allowing you to personalise breaks to your schedule. And who knows, with the positive effect it can have on brain function, long, arduous days at work could soon be a thing of the past.
MEET THE CREATOR Azamat Salakhov, also known as Axo Sal, is the CEO of ZALAB – the software-developing company behind Break Time. His inspiration to create the app came about after reading scientific research widely publicising the negative effects of being physically inactive. From this, he decided to create an app that enabled people to move around every so often and do some physical activity – something he says will go a long way to improving health in the long run. He also believes there should be an emphasis on employers to highlight the effects of sitting down for too long each day. He said: “Fatigued, unhealthy employees are not productive so I encourage employers to educate themselves and their employees about the dangers of long-term physical inactivity. Group breaks could be
incorporated for employees to have fun and do some physical activity together – the regained energy will really benefit the business.” Sal and his team at ZALAB have designed the app for everyone. Whether it be office workers, school children, those on a weight loss journey or blood clot sufferers, it has been designed to provide an alternative to having to buy a smartwatch for the same function. Break Time provides another example of how technology is helping to shape healthcare and Sal believes people having the ability to gather data about their own health can only be a good thing. He said: “Technology allows individuals to gather personal health data and gives them actionable solutions on how to improve it. There are so many exciting ways technology is already helping the healthcare industry and this will continue to develop.”
Get your Break Time started…
WHICH ACTIVITY WILL YOU CHOOSE? • B uzz – a simple buzz notification on your phone • Music – have a quick jig to your favourite songs • Workout – some short exercises to get your blood pumping • Eyes – simple exercises for effective eye relief • Yoga – some relaxing stretches to break up your day • Website – a website of your own choice
BREAK TIME BREAKDOWN • A bsolutely free • Five-star user rating • Research-focused
JOIN THE TEAM BEHIND THE PHILOSOPHY… • G et physical • Create movement • Improve your health
Time spent sitting down (hours per day)
Over how long a period of time
As soon as you sit down
• D ecrease in electrical activity of muscles • C alorie burning rate goes down to 1 calorie/min
• 5 0% drop in artery dilation • D ecreased blood flow around the body
• 4 0% drop in ability of insulin to uptake glucose • Increased risk of Type 2 diabetes
• I ncrease in LDL cholesterol and decline in number of
fat-digesting enzymes leads to weight gain
• M uscles break down and lose ability to contract efficiently
• L ess blood is pumped around the body to the heart • A lso leads to a decrease in brain function which results in bad moods
• 6 –7 year reduction of life expectancy • 6 4% increased risk of heart disease • 3 0% increased risk of prostate or colorectal cancer
Click here to download the app for free now: zalab.surge.sh/breaktime
RESEARCH MEET THE TEAM NEWS
The Importance of Social Media in Science
he face of communication was forever changed when Tim Berners Lee first invented the World Wide Web back in 1989. Since then, social media channels such as Facebook, Twitter and YouTube have taken over as the most popular and effective method for communicating information to the wider public, wherever they are in the world. While certain celebrities may have tainted the name of social media through excessive selfies, its use is arguably more important within the world of scientific research, especially when communicating correct, factual information directly to the public. Alastair Cook, our social media guru here at Research Features, sat down with us to discuss how important having a social media presence is for the modern-day researcher. Hello Alastair! Let’s get straight to it – why is utilising social media so important in science? What benefits can it provide? What social media has given us is the ability to access and connect with an audience on an individual level. Scientists are now able to see the direct impact their work has on the general public – whether it be educational or otherwise. This can especially benefit people who have dedicated their life, or a lot of their time, into a specific field of science. Using social media, researchers can connect with people who have the same level of passion for their work, and share their knowledge with them directly. So for scientists looking to build up their presence on social media, how can they use these channels more effectively? Social media can be quite a daunting place to step foot in. You have to realise that whatever you put out there will be out there forever and can impact how you are perceived. I think it’s important to establish your tone first – you don’t want to come across too serious or too dry. Sarcasm is another thing to avoid, as it’s quite hard to pick up on over text unless someone knows you. Which social media channels would you recommend scientists use when communicating their research to the wider public? In terms of connecting with the general public, Twitter is the most effective. People will follow you based on your work and the conversations you begin. It also allows you to interact easily with the general public, your peers, institutions and even media agencies if you’re looking to gain more exposure for yourself and your research. Are there any scientists on Twitter you would recommend following the example of? My interest in science runs quite deep so I follow a lot of different accounts, but I’d say my three favourites are Neil deGrasse Tyson, Brian Cox and Jennifer Oullette.
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Social Media for Scientists RSM was born out of multiple conversations with researchers who see a real benefit in connecting with a broad audience over an ongoing basis. Social Media can now be considered one of the most prominent and important engagement tools of the modern era. We help you get the ball rolling and can even provide long term Social Media Management support.
Start your Social Media journey now: www.researchsocialmedia.com
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Research Features - Issue 101 Making complex science beautifully accessible