By April Cashin-Garbutt

Understanding and addressing mental and neurological disorders is an urgent need, with hundreds of millions of people affected worldwide. Neuroscience has a major role to play, but how can industry and academia work together most effectively to tackle these challenging unmet needs?

The ‘Building Bridges Between’ initiative

The Sainsbury Wellcome Centre is pleased to partner with the British Neuroscience Association (BNA) on the ‘Building Bridges Between: Industry and Academia’ (BBB) initiative. Following on from the thought-provoking webinar with Sir Mene Pangalos, Executive Vice-President R&D BioPharmaceuticals at AstraZeneca, in Autumn 2020, the BNA recently organised several fascinating BBB activities at the 2021 Festival of Neuroscience.

A principal goal of BBB is to foster collaboration between neuroscientists in industry and academia for information exchange through workshops and networking. Dr Anne Cooke, Chief Executive of the BNA, opened the first BBB session at BNA2021 by sharing the five main aims of the initiative:

• Increase understanding between the two sectors and build connections between individuals and organisations
• Foster discussion and knowledge-exchange to better facilitate scientific translation
• Increase credibility in neuroscience with regards to reproducibility, replicability and robustness of neuroscience research, emphasising the BNA’s core theme of ‘Credibility in neuroscience’
• Raise awareness of the importance of industry and the commercial sector in advancing neuroscience in the UK and its societal benefits
• Support career development for academic members crossing over into industry and vice versa
   

How to improve translation between industry and academia in neuroscience?

The ‘How to improve translation between industry and academia in neuroscience?’ workshop was chaired by Professor Tom Otis, Chief Scientific Officer at SWC, who previously worked at Roche where he was in charge of early drug development for neurodevelopmental disorders and psychiatry. Tom was joined by four distinguished leaders and innovators in industry-academia partnerships: Sir Mene Pangalos, AstraZeneca; Dr Eva Loth, Kings College London; Dr Justin S Bryans, LifeArc; and Dr John Huxter, Transpharmation Ltd.

Referring to his scientific training as a neuroscientist, Sir Mene Pangalos, Executive Vice President and Head of Biopharma R&D at AstraZeneca, talked about the importance of translation and the strategic areas AstraZeneca have been concentrating on to turn science into medicine. His key take home message was to focus on the quality of research rather than the quantity. Under his leadership, R&D teams at Astra Zeneca have developed a framework to identify those programmes with a higher probability of translating science into differentiated medicines. 

This so-called ‘5R framework’ is designed to increase productivity by:

1. Identifying the right target
2. Making sure the molecule gets to the right tissue where it is needed
3. Ensuring the right safety with minimal side effects
4. Selecting the right patients that will benefit
5. Defining the right commercial value and future viability

By implementing the 5R framework, AstraZeneca have managed to increase their success rates above industry average for the number of molecules that progress from clinical development through to launch as a medicine. Accelerated as a consequence of the pandemic, Sir Pangalos shared how AstraZeneca have recently added a 6th theme: embedding the right digital solutions to improve efficiency and deliver quality gains to make sure the molecule gives the maximum benefit to the patient in terms of outcome.

In the Q&A following his talk, Sir Pangalos was asked about a range of topics including target selection in neuroscience indications. In response, he focused on the importance of human genetic validation and the need to bring together all the data (including in vitro, in vivo, preclinical, human and clinical) in an unbiased way to give more or less confidence in the target. He emphasised the need to try to both prove and disprove a hypothesis and avoid the pitfall of believing a hypothesis too much. 

Sir Pangalos also emphasised that publishing in industry is as important as in academia as it allows academics to read more about what scientists at AstraZeneca are working on and encourage collaborations where applicable. Collaborations, in Sir Pangalos’ view, are crucial for industry to go from setting personal bests to world records.

A model example of collaboration between industry and academia was shared by Dr Eva Loth, Reader in Psychology, Kings College London. Dr Loth talked about the EU-AIMS and AIMS-2-TRIALS consortia –  large-scale projects with the aim of studying the biology and treatment of autism spectrum disorders. She shared the importance of learning each other’s language and building trust, both between scientists in academia and industry but also with people who have autism spectrum disorders. 

Dr Loth outlined the Longitudinal European Autism Project (LEAP) where academia, industry, and patient groups came together to achieve something bigger and bolder than what had been done before. The LEAP study was unprecedented both in terms of the scale and the level of deep phenotyping achieved in a large population of individuals diagnosed with autism spectrum disorder. She also shared the positive impact on PhD students who were part of the multidisciplinary consortium. These early career researchers are now actively leading on a new platform called ECRAN for training the next generation of researchers. The platform focuses on exchanging experiences, peer-to-peer monitoring, mentoring and conducting training workshops and lab exchanges. Dr Loth commented on how growing up in such a culture has changed their perspective enormously.

The importance of strong partnerships between academia and industry was also emphasised by the next speaker, Dr Justin S Bryans, Executive Director of Drug Discovery at LifeArc, a UK-registered medical research charity focused on catalysing translational science to develop new medicines. Dr Bryans began by highlighting academia as a rich source of targets and new ideas which form the basis for many drugs. He noted that strong partnerships are key to maximising this potential between academia and industry and shared his thoughts on the crucial ingredients:

• A common purpose – all parties have the same patient-centred endpoint in mind; an agreed plan of how to progress the work with clear allocation of activities and a defined timeline for delivery of owned activities that are adhered to
• Each party brings something significant to the table – the individual components should add up to more than any one party can do alone and each party can see the value in the others
• Each party gets something significant from the partnership – funding to support academic labs; downstream rights should be equitable; publication potential is critical for academics and it is imperative that the academic remains engaged with the programme – it could be their life’s work!

The final speaker of the session, Dr John Huxter, Cognition Area Lead / Scientific Liaison at Transpharmation Ltd., shared his thoughts on the pitfalls and prospects for cognitive assays in preclinical research. The first pitfall he warned against was, in an age of proteomics, AI and digital health, forgetting that cognition matters. Dr Huxter highlighted how cognition is often the primary endpoint in clinical trials and cognitive assays provide a more complete, system-wide picture of treatment effects. The other pitfalls Dr Huxter shared included failure to fully understand your assay; failure to understand your species in terms of the ethological relevance of the task; and failure to consider the affordability of your task in terms of the labour required.

For successful translation, Dr Huxter argued the key is to do good science and know your model, assay and clinical endpoints. If you don’t know them really well, Dr Huxter recommended collaborating or potentially outsourcing. In addition, he advised automating tasks where possible, including non-behavioural endpoints, and encouraging the use of objective measures in clinical trials.

The translation workshop was followed by lively breakout discussions in three main groups: credibility and reproducibility in neuroscience; careers in academia and industry; and the design and reporting of animal research to improve reproducibility. The BNA2021 Festival content, including these online discussions and recordings of the virtual BBB sessions, will be available on-demand for the next 4 months. For further details visit: https://meetings.bna.org.uk/bna2021/

Translational neuroscience for mental health research

Continuing the theme of translational collaboration between industry and academia, the BBB initiative ran a panel discussion on ‘Translational neuroscience for mental health research’ during the BNA2021 Festival of Neuroscience. This special session on mental health was chaired by Professor Tom Otis who began by sharing some staggering statistics on the unmet needs of those suffering from mental health disorders. Studies in many countries estimate that at least 1 in 5 adults live with serious mental illness. According to The Lancet, in 2010 mental illness resulted in a global loss of about 185 million disability-adjusted life years. Furthermore, the World Health Organisation, estimates more than 250 million people worldwide suffer from depression and approximately 800,000 people die due to suicide every year.

This urgent need to understand and address mental health problems has motivated Wellcome, a large-scale biomedical funder, to recently designate mental health, along with infectious disease and climate, as a key component of their strategy to find solutions to worldwide health challenges. Professor Miranda Wolpert, Director of Mental Health at Wellcome and Professor of Evidence Based Practice and Research at UCL, joined the BNA2021 BBB panel discussion where she outlined Wellcome’s approach, the funding available and the challenge of bridging the gap between basic neuroscience and translational mental health interventions to address the unmet needs.

From a funding perspective, Professor Wolpert highlighted two primary routes. Firstly, the Discovery Science schemes that are open on a rolling basis for early career researchers, those in career development stage and those with a more established career that are doing large-scale projects. Secondly, the mental health challenge area that will be putting out calls and commissions for grants and contracts globally.

In addition to funding, Professor Wolpert stressed Wellcome’s role in convening and bringing together new fields and researchers that don’t otherwise have access to one another. She highlighted Wellcome’s role in advancing learning through pulling together best knowledge. 

One particular area Wellcome are focusing on is why there are so few effective treatments for mental health problems. Professor Wolpert shared Wellcome’s hypothesis of siloed communities within mental health who aren’t learning from each other as much as they might. They hope to break down these siloes and bring new communities together by focusing on a common language and core metrics to enable comparisons across different studies.

Another challenge area Professor Wolpert highlighted was the focus on small samples from Western, Educated, Industrialised, Rich and Democratic (WEIRD) countries. Wellcome want to ensure that research looks at populations beyond those WEIRD samples so we have much more globally diverse populations. They also want to move beyond the patient paradigm to look at populations outside the clinic, as there is much to learn about how people recover, or don’t recover, from mental health difficulties who have had no access to mental health services at all.

Wellcome are also interested in thinking about the narrative around the different ways we can intervene to address mental health difficulties as their vision is a world in which no one is held back by mental health problems. Professor Wolpert’s ask to the community was to understand how neuroscience fits in relation to the mechanisms and modes of action of mental health interventions that will help people move on in their lives.

This focus on mechanisms was shared by the next panellist Professor Catherine Harmer, Professor of Cognitive Neuroscience, University of Oxford. Professor Harmer’s research largely focuses on the mechanisms of antidepressant drug action and potential mechanisms across different treatment modalities and their combinations. 

An experimental psychologist by training, Professor Harmer became interested in psychopharmacology. She realised there was a huge gap in understanding between the two fields as drug treatments in mental health are typically considered at a biological level but other types of interventions in mental health, such as psychological interventions, are analysed from a cognitive perspective. Given this, Professor Harmer shared how she started a series of studies exploring how antidepressants affect the cognitive processes that we know are important in depression. 

Professor Harmer found that antidepressant drug treatment can affect negative affective biases, where patients with depression are more likely to focus on, interpret and remember more negative information over and above more positive cues. One of the striking observations Professor Harmer shared was just how quickly these effects came about. Her team started to see effects of antidepressants on emotional processing even after a single dose, long before individuals would notice any improvement in their clinical symptoms. This led Professor Harmer to suggest that perhaps antidepressants don’t work by reversing problems with mood and other symptoms of depression directly, but instead by subtly changing how we deal with emotional information.

This approach has a number of potential applications. Firstly, Professor Harmer and team are investigating whether they could use this early change to emotional processing to predict response to treatment. This could be beneficial for predicting those likely to be non-responders so those individuals don’t have to wait for extended periods of time and instead can access alternative treatment options. Secondly, Professor Harmer hopes this approach could be used as an experimental medicine model to screen, predict, understand new treatments in development. The aim is to improve decision-making in how these treatments are developed and reduce subsequent failures in randomised clinical trials. 

This focus on evidence-based innovation was also shared by the final panellist, George Goldsmith, Co-founder of Compass Pathways, a mental healthcare company researching how psilocybin, the active ingredient of psychedelic mushrooms, could help people with treatment-resistant depression. Mr Goldsmith talked about the opportunity to improve patient experience in mental health, both in terms of access to care, but also in terms of how their own narrative and world views shape their lives. At Compass, teams are working on whether there are there ways to intervene on multiple different levels to change outlooks. Specifically, they are focused on the potential to couple a medicine and psychiatric therapy to help people with treatment-resistant depression and they have received FDA breakthrough therapy designation for this approach and are in phase IIb trials in ten countries.

In the panel discussion that followed, Professor Tom Otis, Professor Miranda Wolpert, Professor Catherine Harmer and George Goldsmith discussed a range of topics including whether we need to understand how mental health disorders function at the level of neural circuits in the brain in order to advance treatments. Professor Harmer argued that the field has been attempting to do this for a long time, however it is very challenging to tie down definitive circuits of diagnostic relevance to mental health conditions. Instead she feels we are better placed to understand some of the underlying circuit mechanisms of how effective treatments work and to consider these against the backdrop of what we know about the disorder as there probably isn’t one underlying biology of the diagnostic categories as they stand now.

Mr Goldsmith added that in addition to understanding the mechanism of action, it is also important to focus on the mechanism of change and to take a whole person approach by bringing together multidisciplinary teams. Professor Wolpert also agreed and raised concerns over whether the diagnostic categories could potentially hold researchers back when trying to link to neural circuit mechanisms. From an SWC perspective, Professor Tom Otis reinforced that we will continue to work on circuits involved in key behaviours and help shed light on how the brain functions normally and how it malfunctions in the context of neurological and mental health disorders.

A recording of the BNA panel discussion will be available on-demand for the next 4 months. For further details visit: https://meetings.bna.org.uk/bna2021/

References

• https://www.who.int/news-room/q-a-detail/mental-health-neurological-disorders
• https://www.who.int/en/news-room/fact-sheets/detail/mental-disorders
• https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2813%2961611-6/fulltext
• https://www.who.int/news-room/fact-sheets/detail/depression