One of the most unique and attractive aspects of this PhD Programme is the fact that we are given the opportunity to design our own PhD projects. This is very different to most PhD projects or programmes where a variety of PI’s might pitch projects and you would pick your favourite, which is how we selected our three mini-projects in Year 1. For our PhD projects we were left to our own devices, to meet with potential supervisors, discuss our ideas and design our own projects; an exciting but daunting task! With six of us in the programme going through this process at the same time, we each had our own unique experience, and each came across different hurdles along the way. Some of us ended up back in labs were we had done a mini-project, whilst others ventured into unknown territory. Some of us returned to areas or techniques we were familiar with, and others pursued areas they’d never worked in before but had been inspired by clinic visits or seminars during Year 1. The process of deciding on a project was very different for each of us, with some of us focusing on lab groups that we were interested in, and others focusing on areas they really wanted to work in.

For example, Rebecca managed to completely design her own project, bringing her two main interests together, even though no one in Edinburgh was working on that specific area. She says: “I come from a background working in mental health services with people who have suffered childhood abuse and neglect. This was an area I wanted to be able to contribute towards with my research, and I’m really pleased to have carved out a project for myself which allows me to do that. Throughout year 1 of the programme, the idea of inflammatory contributions to many different neurological and psychiatric illnesses came up as a repeating theme. This grabbed my interest as well, so I focused my search for a topic onto work covering the overlap between the two. Nobody in Edinburgh specifically works on this field, although there has been a good amount of background work into stress and inflammation, but the real advantage of bringing our own money to the lab in which we want to do our PhD work is that you’re not 100% tied to their existing research grants. This has allowed me the freedom to propose a project that’s really well suited to my interests and motivations. The challenge behind that is finding the expertise within Edinburgh to guide me through the project. Thanks to the programme’s encouragement to choose a larger supervisory team than the standard supervisor + co-supervisor duo, I’ve been able to bring different areas of expertise together which will hopefully allow me to access the support I need throughout my PhD.”

In a very contrasting way, Robert changed his mind completely and moved away from his interests pre-PhD and chose a project in an area he had never experienced before moving to Edinburgh for this PhD programme: “Before I started on this PhD programme, I thought I wanted to embark on a research project relating to medical devices, such as biomaterials, and how they may repair the brains of individuals with diseases such as Parkinson’s disease. I had experience in the fields of nanomedicine and biomaterial design and while I am still passionate about those areas, this PhD programme inspired me to change direction to a new area which I have embarked upon for my PhD project. Thanks to the many exciting experiences and research projects we were exposed to in our first year, I decided to embark upon a PhD using data analytics and machine learning for the development of a blood-based test to predict dementia. I am very grateful for my first year on this programme as I would not have discovered my new passion otherwise and I feel that I will leave with a much broader skill-set and scientific knowledge than if I had stuck to a traditional PhD route.”

Similar to Rob, I designed a project with a P.I. that I had worked with before, but even while working on the topic for my third mini-project, I still wasn’t sure what I wanted to do for my PhD! I had chosen this PhD programme because I was interested in a wide range of neurological disorders, and with every clinic visit or seminar we had I became interested in more and more topics. In our third semester, I became very interested neuroimmunology, especially in the idea of therapeutically targeting peripheral immune cells as they travel to the brain. Because of this new-found interest I spoke to a few P.I.’s working in a range of disorders from autism to schizophrenia to stroke where I could design a neuro-immunology based project. All of these projects were really interesting, so I was faced with a tough decision, but I ultimately decided to continue working on haemorrhagic stroke, in the lab where I was based for my third mini-project. Whilst the fact that I really enjoyed the lab environment and got along great with the P.I. helped my decision, what really decided it for me was that the research field of intracerebral haemorrhage in Edinburgh was really escalating. With a great resource of post mortem brain tissue available, and a new trial on acute patients about to begin, I felt I was able to design a truly translational project and was able to create a multi-disciplinary supervisory team.

Whilst the overall experience was probably the most challenging thing we faced in Year 1, I think we’ve all come out of it with fantastic, translational projects that we’re all excited to get our teeth sunk into. The other benefit of designing our own PhD projects is that we gained a lot of confidence. By approaching so many senior academics to discuss the work that we were designing, we were spoken to as an equal, and I think that experience has been invaluable for us as we face into our PhDs now, were many more challenges will undoubtedly come!

Take a look at the variety of PhD projects we’ve designed here-we’ll update you with the results in 3 years!!

Rebecca:

Childhood adversity is associated with a raised risk of psychiatric illness, including mood disorders, in adulthood. This is detrimental to the wellbeing and productivity of affected individuals, and costly to health and social services. The type of early-life stress associated with adverse childhood experiences has been found to suppress the immune system, leaving it more vulnerable to illness and infection. Mood disorders are linked to whole-body inflammation. Inflammatory changes in the body are associated with onset of depression; also, depressed people have a higher level of inflammatory markers in their blood than non-depressed people. This suggests that inflammation may play a role in causing and maintaining mood disorders. This makes it possible that as well as directly contributing to the risk of adult mood disorders, childhood adversity makes you vulnerable to illness, which adds a second burden of risk through inflammatory pathways. Identifying the changes in the brain associated with this ‘cumulative risk’ could help identify the best treatment for patients with a history of both childhood adversity and inflammatory illness. This PhD project aims to identify those brain changes at a cellular and molecular level in an animal model, and on a structural level using brain imaging from humans.

Rob:

Dementia refers to a group of disorders in which nerve cells within the brain deteriorate. Changes in the levels and function of certain proteins within the body promote the development of diseases, such as dementia. However, the reasons why these changes in protein profiles occur are poorly understood. Therefore, we aim to understand the factors which contribute to such changes in people with dementia and those who are at high risk for developing the disease. This may allow for a better understanding of how the disease works and may also help to predict who will develop dementia prior to disease onset.

Firstly, I will identify which proteins are different in the blood of individuals with low risk for dementia when compared to those with high risk (based on family history and genetics). Subsequently, I will determine the genetic and epigenetic architecture of these differentially-expressed proteins. I will then determine whether such proteomic changes are reflected in brain tissue donated by dementia patients and donors who did not have dementia. Using these data, I will create a proteomic signature of dementia risk. Together, this doctoral research will reveal which proteins are associated with dementia and help understand why such changes occur.

Caoimhe:

Intracerebral haemorrhage is the subtype of stroke caused by a blood vessel bursting, leading to bleeding in the brain. This bleeding not only causes a physical disruption to the brain, but also triggers a substantial inflammatory response. This involves the activation of microglia; the resident immune cells of the brain, as well as the infiltration of immune cells from elsewhere in the body. These cells are known to have both detrimental and beneficial effects, as some increase the toxicity in the brain, whilst others clear up the bleed and surrounding dead cells, thereby reducing further brain injury. There is an urgency to understand the exact role of these cells after intracerebral haemorrhage, as 40% of patients die within the first month due to the lack of surgical or medical treatments available. Using valuable human post-mortem tissue from haemorrhagic stroke patients, I hope to better understand how these immune cells are contributing to the clearance of the bleed. Furthermore, I will test pharmacological treatments in rodents that are aimed at augmenting the beneficial functions of these cells to determine whether such treatments can improve recovery after an intracerebral haemorrhage, which would provide evidence for the use of these drugs in patients.

Anders:

Depression is one of the most prevalent mental health disorders and the leading causes of disability worldwide. Increased poverty and fewer years of education have been associated with a higher risk of developing depression, but evidence from different studies has been inconsistent, severely limiting opportunities for causal inference and intervention.

To address this inconsistency, I first propose to investigate the associations between social deprivation, and depression using epidemiological data, including large longitudinal cohort studies providing rich psychiatric, social, economic and genetic data on >300K participants. Secondly, I will leverage the genetic data available to make stronger causal inferences between social deprivation and depression. Finally, I seek to examine potential mediators for any significant causal relationships, using brain and illness-related traits recorded in these datasets.

Findings will contribute to discovery of risk factors for depression, deprivation and their intersection helping to stratify diagnosis and inform policy aimed at reducing depression and socioeconomic disadvantage, thereby translating research into practice. By identifying the genetic architecture of depression and deprivation as well as potential mediating effects of brain anatomy, we will begin to understand the biological pathways involved and contribute to the discovery of new drug targets and more targeted interventions.

Fenia:

Multiple sclerosis (MS) is a chronic disease of the brain in which there is damage to the protective covering of the nerves, called myelin, resulting in disability. In MS, the connections between nerves, termed synapses, are also damaged. We think that special immune cells of the brain, known as microglia, remove synapses, so that nerves cannot communicate with each other, thus worsening disability. What causes these microglia to damage certain synapses, why and how this happens is not yet known in MS.

My PhD will study how microglia cause synapse damage in animal models of MS and brain samples from MS patients. I will examine the types of synapses that are damaged, the location of the damage in the brain, and how microglia are involved. I will investigate how synapses are tagged for microglia, and how microglia recognise and remove them. I will then attempt to alter the microglia to make them less damaging, in an effort to prevent synapse damage in MS.

Rana:

Schizophrenia is a highly heritable, debilitating neurodevelopmental disorder that has a world-wide prevalence of 1%.  Genetic rearrangements, known as copy number variants (CNVs), were shown to account for a significant portion of Schizophrenia’s genetic liability. CNVs are deletions and duplications which result in a deviation from the normal number of copies of a given gene segment. CNVs in the NDE1 gene on Chromosome 16q13.11 lead to an increased risk of Schizophrenia. However, the underlying molecular mechanisms by which these deletions and duplications lead to a major psychiatric disorder remain largely unknown. I aim to investigate the effects of CNVs in Chromosome 16q13.11 on cortical development using in-vitro, miniature organs resembling the growing brain; known as cerebral organoids. Organoids are derived from stem cells obtained from patients carrying the mutations and their unaffected family controls. I will study whether key biological processes essential for the correct development and patterning of the brain, such as neuronal migration and proliferation of neuronal progenitors, are altered in patient organoids using a combination of time-lapse imaging, cell-cycle and cell-viability assays. This work will help explain the roles of NDE1 in human corticogenesis and provide mechanistic insights into how 16p13.11 CNVs are implicated in psychiatric illnesses.

~Caoimhe Kirby

Designing our own PhD Projects: Pressure or Privilege / Wellcome Trust 4 Year PhD in Translational Neuroscience Blog by blogadmin is licensed under a Creative Commons Attribution CC BY 3.0