Jack Mellor is a Professor of Neuroscience at the School of Physiology, Pharmacology and Neuroscience at the University of Bristol. His work investigates the fundamental neural processes which underpin cognition, and which have profound implications in the treatment of many neurological and psychiatric disorders. We caught up with him to find out about his research journey, and how his lab collaborates with other departments, clinicians and industry partners.
Behavioural adaptation – Synaptic plasticity
Jack’s group focuses on the brain processes that enable us to learn and remember new information about our environment, and then adapt our behaviour appropriately. At a simple level this might be remembering where you left your bicycle but it can also apply to negative emotions associated with traumatic events and avoidance of associated places or objects. A process known as synaptic plasticity is fundamental to this adaptive behaviour.
It’s the process whereby a chemical signal is released from the synapse of a neuron, and diffuses across to a target neuron (or another type of cell). This signal can excite, inhibit, or otherwise modify the behaviour of the target cell. Over time, the amount of chemical signal that gets released, or the target cell’s response to it, can be modified based on previous activity. This adaptation at a cellular level then enables the brain and ultimately us an individuals to adapt our behaviour.
“Experience is so fundamental to shaping who we are as individuals, and how we contextualise our experiences is implicated in many neurological and psychiatric disorders,” explained Jack. “Memory is fundamentally dependent on the behavioural context of learnt information, and in my lab we aim to investigate the contextual factors that are important for the encoding of memory by synaptic plasticity at a neuronal circuit level.”
History
Professor Mellor graduated in neurophysiology in 1995 from the University of Cambridge, and stayed on there to study for a PhD under Professor Andrew Randall on the biophysics and pharmacology of inhibitory synaptic transmission at the MRC Laboratory of Molecular Biology.
Following his PhD, Jack worked for a short while at the Department of Science and Technology. “I was doing policy work, just to see whether or not that was something I was interested in. It was pretty fun, but I think ultimately it wasn’t where my strengths lay!”
Inevitably, the lure of returning to academia was too strong, and Jack accepted a position at Roger Nicoll’s laboratory at the University of California, San Francisco. “The US postdoc was funded by the Wellcome Trust; I was awarded a fellowship which funded me for two years out there, and another year back in the UK. So in 2002 I decided to head to Bristol to the world leading centre in neuroscience research that was there at the time.”
In Bristol, Jack was initially working in Professor John Isaac’s laboratory, before being awarded an MRC funded Career Development Fellowship which enabled him to set up his own group in 2004; more fellowships and a lectureship followed.
In 2011 Jack received an ‘Institutional Strategic Support Funding’ award from the Elizabeth Blackwell Institute with funding from the Wellcome Trust. Jack says: “The funding was designed to support me and give me time to prepare for applying for further Wellcome funding which I subsequently did. It really helped me develop some ideas I’d been working on at the time.” The follow-on application was successful and Jack was awarded a £1.1 million grant to understand how one of the brain’s key neurotransmitters called ‘acetylcholine’ influences brain activity. In collaboration with the pharmaceutical company Eli Lilly & Co., the team looked to translate the findings into new treatments to combat dementia and schizophrenia.
The Mellor Lab
“I’ve always been interested in the electrical properties of nerves and how they communicate and electrical measurement was my training” Jack continued. “At the time I was trying to evolve into neuron imaging and in particular calcium imaging [a technique which looks at the movement of calcium ions within tissues and cells issuing calcium-dependent fluorescent markers]. Part of the ISSF funding went towards developing these capabilities. This slightly different approach gave us an extra dimension to investigate how neurons and synapses operate”.
Even now, the group is still electrophysiology focused – but also performs a considerable amount of in vivo calcium imaging. “This way, we can measure and locate many neurons at once. It helps us to further understand the neural basis of cognition and how networks of neurons link up and then adapt their firing in order to allow us to adapt our behaviour.”
Collaboration is key
Professor Mellor’s group is involved in extensive collaborations with academic, clinical and industry partners. The collaborative work focusses on how network function within the hippocampus is modified by synaptic plasticity, and investigates novel compounds that might modify that plasticity – which might in turn lead to new drugs.
Simultaneously, the lab is investigating how these neural processes are altered in psychiatric and neurological disorders, leading to disruptions in cognition. Understand these processes – and the neuromodulators in question – has the potential to lead to new therapeutic avenues, and better treatments for a variety of disorders.
Mechanisms
Collaborations come together in a number of ways, as Jack explains: “We either seek out potential collaborators whose expertise might feed into what we’re working on, or else they might approach me with ideas,” said Jack. “I really enjoy a team approach to science and always appreciate the value of integrating different perspectives and ideas into our work. I have reached out to many collaborators in the past and am always surprised by how receptive most people are. It doesn’t always work but most of the time everyone gains something!”
The Mellor Lab has particular expertise in cholinergic drugs and muscarinic drugs, some of which have been moving through various drug-development pipelines over the years.
“There have been some just licensed recently,” said Jack, “which are quite interesting, in that they’re very similar to drugs we’ve worked on – and published on – with drug companies. I wouldn’t say that any of that work with us thus far has directly contributed to drug development, but I think the body of work in general is important. And it’s been interesting to gain insights into how drug companies work and what aspects of our research are important to them.”
Reliable and robust
Jack contends that a key part of the relationship between the Mellor lab and industry relies upon ensuring that the research is reliable and robust enough that drug companies feel confident, and trust in the relationship:
“I think that the ability to do reliable research is a key factor for external collaboration – we have to demonstrate the robustness of our output very clearly to potential collaborators.”
“At the moment my lab is researching a derivative of psilocybin in various assays that we run: drug companies use our expertise to gain information to help them in terms of formulating how they’re going to use these drugs and what sort of trials they want to undertake.”
Quid pro quo
What does the lab gain from giving their industry partners the benefits of their expertise? As well as funding, in the past they have also allowed post-doc researchers to be embedded at pharmaceutical companies, and they also fund PhD students.
“I’ve got a couple of PhD students at the moment who are part funded by pharmaceutical companies,” said Jack, “and overall, I think it’s sometimes good to have the support of a financially motivated institution to demonstrate that there is a wider value to the work beyond simply the intellectual interest.”
Mellor futures
The Mellor lab is presently focused on a number of projects investigating the genetic risk factors involved in neurodevelopmental disorders, specifically schizophrenia – but which might also have relevance for other disorders. In 2023 they were awarded £2.1 million to study the biological changes that occur in schizophrenia. The award from the Medical Research Council will help scientists understand how genetic mutations in multiple different genes lead to common biological and cognitive changes and identify new therapeutic targets. The project forms a multi-disciplinary and cross-institutional partnership between research teams led by Professor Mellor with Dr Mike Ashby, Professor Jon Hanley and Professor Emma Robinson at Bristol, Professor Jeremy Hall at the University of Cardiff and Professor Dimitri Kullmann at University College London, along with clinical research teams led by Dr Mike Carter and Dr Kasia Sieradzan in Bristol.
“This work has strong links with epidemiology. We’re considering ways of processing large data sets and trying to work out where risk occurs and how it leads to the underlying neurobiology. I’m interested in the underlying neurobiological principles of these things and the sorts of data you can pull out from large genetic data sets. We’d hope to use the data to formulate hypotheses that we can then test in the group.
Unknown unknowns
Jack is also at the preliminary stages of projects investigating the effects of uncertainty on cognition and behaviour, as he explained:
“This project looks at how the brain processes different forms of uncertainty, and how we need to adapt our behaviour to cope with these, as well as the neurological representations of that uncertainty. Essentially, how your representation of uncertainty evolves and therefore what you decide to do about it.
“There’s a famous 2002 saying by (US politician) Donald Rumsfeld: ‘…there are known unknowns; that is to say we know there are some things we do not know. But there are also unknown unknowns—the ones we don’t know we don’t know’.
“Rumsfeld got a lot of stick for that, but he was articulating a fundamental concept, which often doesn’t go down well from a politician. If you know that something is unknown, you don’t necessarily have to adapt your behaviour – but if something happens that is an unknown unknown – that is, something you were previously unaware that you didn’t know – then you’ve got to change: you modulate something. The difficulty we have in everyday life is identifying and distinguishing between these types of uncertainty, and adapting our behaviour accordingly.”
Overlaps
Indeed, there is a certain amount of overlap between the existing investigations into genetic risk and neurodevelopment disorders, and investigations into uncertainty.
“Many of the problems that people have in developmental disorders involve managing uncertainty,” said Jack, “and a lot of the treatments potentially involve neuromodulatory systems such as acetylcholine, dopamine, serotonin or noradrenaline, which are the systems that we study. So the projects link up quite nicely together.”
Working the intersection
Jack has always enjoyed working as part of a team and particularly working between disciplines. He was involved with an Elizabeth Blackwell Institute fellowship scheme where Jack supervised Dr Sonam Gurung who was awarded the Elizabeth Blackwell Institute Discipline Hopping Fellowship – a scheme which encouraged researchers finishing their PhD to do an extra six months to a year in another discipline – and was given an opportunity to extend her PhD studies on the biochemistry of GluK2 editing in his lab.
“I’ve worked at the intersection of biochemistry and physiology for many years,” he said, “and now we’re starting to work more at the intersection of animal behaviour and psychology.”
Jack believes that Institutions, such as the Elizabeth Blackwell Institute, that enable – and indeed encourage – interdisciplinary work are vital to supporting the multidisciplinary landscape that is so important in research.
Elizabeth Blackwell Institute continues to support interdisciplinarity in health research as part of its core mission. Find out more about what we do.
