David Sweatt, university of Alabama
Kat - This month I’m reporting back again from the Genetics Society Spring meeting, which was held at the beginning of April at the Royal Society in London. Called “Psychiatric Genetics: Pathways and Prospects”, the meeting featured talks from leading scientists from around the world, discussing how genetic research is shedding light on mental illness and improving life for sufferers.One speaker was Dr David Sweatt, from the University of Alabama, who is researching one of the most fundamental questions in brain research - how we make memories.
David - We’re interested in how experiences especially learning experience impacts gene readout in the brain. That type of gene readout is known to be necessary to make long term memories. And so, we’re interested in the impact of experience on gene transcription in the brain and in particular, focusing on a set of mechanisms call epigenetic molecular mechanisms - those are things like chemical modification of DNA and regulation of the 3-dimensional structure of genes in the brain - and have found that those mechanisms are an important regulator of memory-associated, learning-associated experience dependent alterations in gene readout in the brain.
Kat - So obviously, the challenge is, all our brain cells have the same set of DNA, but they do lots and lots of different things and work lots of different ways. How do you start studying these and unpicking what's actually going on?
David - It is very difficult. There are some new types of approaches that we and others are starting to use where for example, you can use transgenes. You can genetically tag a specific kind of cell or a specific kind of neuron for example that you know is involved in forming a particular kind of memory and then use a procedure called fluorescence activated cell sorting to specifically sort out those specific memory associated cells. And then you can look to see whether the molecular changes that you're interested in happen in that actual specific subset of cells in the brain. That's a new emerging technology but it has promise to solve some of this problem that you're talking about.
Kat - So you're literally pulling out the cells that have made a particular memory. That sounds incredibly powerful. Then how do you look at them? What are you looking for?
David - We are most interested right now in looking for direct chemical reactions that occur with the DNA in the brain – a chemical reaction called DNA methylation, cytosine methylation. So, there are enzymes that put a methyl group on cytosines and those methyl groups, when present, are very powerful regulators of gene readout. And so, we’re interested in trying to identify the specific genes and specific types of cells where those changes happen where there's been this actual chemical reaction with DNA to regulate gene readout associated with memory.
Kat - And from what I know of the biology and the chemistry of DNA, this kind of methylation tags, they're usually associated with sort of long term, very static, locking down DNA so genes definitely get switched off. But that doesn’t seem to be what's happening in the brain, is it?
David - Certainly, those types of reactions happen in the brain. They're critically important for keeping a neuron a neuron for example. But it does appear as you said that there's an additional set of mechanisms that can dynamically regulate, put methyl groups on and off of this particular subset of genes that may be important for the plasticity of the cell and how it changes its function in response to a transient signal like a learning event.
Kat - Can you tell me a bit about some of the experiments that you actually do to understand what's going on in the brain? What sort of systems are you using?
David - We try to take an integrated approach and so, almost all of our work involves behaving animals. We use a variety of different behavioural paradigms. Most of them are studying some aspects of learning and memory. We use a variety of spatial learning tests like the kind of classic animal in a maze. We use rats and mice for most of our studies. We use a variety of kind of reward mediated behaviours where the animal learns that if they execute a certain behavioural pattern and they can get a reward. And then we also use some training paradigms where an animal recognises that's in a threatening environment. Clearly, a human’s cognitive function is much more complicated than a rat or a mouse. And so, we’re probably only scratching the surface. But the operating assumption for our work is that there is going to be at least some set of shared molecular and cellular mechanisms that are involved in both animal behaviour and human behaviour.
Kat - How close do you think they are to really understanding how the brain is working at this kind of genetic on and off, what genes are working, what's being switched on when and where?
David - We’re about 1 per cent of the way there I would say. Once you start, you really get in there and use a whole epigenome types of approaches with next generation sequencing, and looking at the whole exome - everything that's being transcribed out of the genome - in memory associated cells and start to then overlay all of the regular kind of transcription factors and everything that's involved. It’s clearly going to be horrendously complex. And so, it’s going to require a lot of heavy lifting in terms of doing the molecular characterisation in terms of the genes and the epigenetic marks that are changing and then a lot of heavy duty computational biology and modelling of that sort of environment - informatics and analysis - to even begin to try and put up together a cohesive, a big picture of the mechanisms reacting with each other and then giving a final output.
Kat - That was David Sweatt, from the University of Alabama.