The most common question I’ve been asked when introducing my work to strangers, friends, and Tinder dates has been “but aren’t mental illnesses…in the mind? What do genes or molecules have anything to do with it?” The answer is, in short, everything. Each of our mental functions is fundamentally rooted in biological processes that can easily be influenced by molecules. This is why an anaesthetist can stop your ability to maintain consciousness, a bartender can help you improve your dancing abilities (or so I tell myself), and the pretty barista at Café Nero can help you wake up in the morning. For millennia, humans have known that certain substances can affect the way we think, act, and even feel. At the Department of Psychiatry we expand on this concept: if events at a molecular level can affect the function of entire cells, and if interactions between cells in the brain determine behaviours and thought patterns, then it is only logical that problems happening at a molecular level will affect your mind.
Bipolar disorder and schizophrenia are both classified as mental illnesses that tend to have a late-puberty/early-adulthood onset, and be devastating to peoples’ ability to function and integrate into society. At an age where most of us are starting our careers, going through our university years, and making personal relationships that will last a lifetime, afflicted individuals are experiencing a world of unfamiliar thoughts and emotional turmoil – with symptoms ranging from hallucinations, paranoia, euphoria, and depression. Despite the best efforts of healthcare professionals, due to a lack of understanding and public education about mental health, as well as the embarrassment and social stigma associated with seeking treatment, many of them never receive the support and help they need. And the worst part? Due to a lack of understanding of the biological causes of these diseases, current therapies are not effective for all of the patients that do seek help.
Less than one hundred years ago, studies on how the mind worked were limited to trial and error and reported case studies. We used to depend on patients walking in to the clinic with brain injuries or with life-altering psychological symptoms, and teams of neurologists, radiologists, and psychiatrists to note down any observed cognitive deficits and atypical behaviours that could be later investigated in a lab. As biologists and psychologists, we would gather around reading and re-reading case reports, desperately trying to piece together the truth from scraps of information left in unkempt databases around the world. Now however, we finally have enough tools and techniques to go the other way: running experiments in the lab in order to understand symptoms of patients in the clinic.
With the advent of faster DNA sequencing technologies, we can look at thousands of genes at a time, and compare data from tens of thousands of patients. With the help of computer scientists and statisticians, we can analyse that data and find out whether certain gene mutations are more or less prevalent in certain groups of populations. With the help of molecular biologists, biochemists, and overly ambitious DPhil students we can look at those genes in greater depth and figure out what they do, and why tiny changes or mutations in those genes might affect the way you process thoughts and emotions. And it is only now, with the collaboration of thousands of these passionate researchers, that we are starting to truly understand how the human brain works, how it can go wrong, and how we can fix it. And in fact, in recent years we’ve managed to identify a gene with mutations that cause increased risk for bipolar disorder and schizophrenia: CACNA1C.
So what is CACNA1C, and if we already know it’s so important then why haven’t we already cured bipolar disorder and schizophrenia? It turns out the CACNA1C gene product is part of the protein complex called CaV1.2, which is found throughout your brain, heart, muscles, and glands. When activated, CaV1.2 opens up and allows a rush of calcium ions to flow to the inside of the cell, where they can bind to other proteins and drive the expression of other genes. Exactly which proteins are activated depends on where CaV1.2 is located in the cell and how long it remains open.
Interestingly, it has been shown that having a risk mutation in the CACNA1C gene causes changes in brain function and cognitive processing even in people that do not have bipolar disorder or schizophrenia. In one experiment, where volunteers had their brains scanned in an fMRI machine while being asked to do a series of cognitive tasks, many of the people with the mutation were able to perform just as well as those without – but some of their brain regions had to work harder in order to reach that same level of performance. In other words, it’s been possible to translate our data from the molecular scale directly to its effects on a whole-brain level. And we’ve only just started. By itself, the CACNA1C mutation only accounts for a small subset of disease symptoms – it’s only when its combined with a series of other genetic, social, and environmental factors that it leads to the onset of mental illness.
So what exactly regulates how CaV1.2 is activated, how do these regulatory processes differ from cell to cell, and how are they affected by people with risk mutations for bipolar disorder and schizophrenia? I could tell you a bit about that now – but it’s a three-year research project, it’s going to take some time to explain it properly. Why don’t we talk about it over a cup of coffee, just the two of us? I know a great place down the road.
– Syed Munim Husain