This is the second – following our interview with Tom Insel in August – of a series of interviews we’re planning with key people in the field, looking at their work and what it says about the future of applied neuroscience. We hope you enjoy them.

Studying the epigenetics of stress is helping us to understand how it can impact individuals differently. "These environment-gene interactions are far-reaching," says Elisabeth Binder, Managing Director of the Max Planck Institute’s Department of Translational Research, "but we are on the right path to grasping their role in a number of psychiatric disorders."

Dr Binder spoke to ECNP about her work, the future of psychiatric research, and its unanswered questions.

You trained as a medical doctor, going on to do a PhD in neuroscience. What prompted you to move into translational psychiatry?
I initially studied medicine, first in Vienna University (Austria) but also at the Universite Libre de Bruxelles (Belgium). There, I took psychiatry with Julien Mendlewicz, one of the founders of psychiatric genetics. His lecture was not ‘regular’ psychiatry; he really brought up a lot of biological psychiatry and genetics in psychiatry.

This really fascinated me. It initiated my wish to continue after my medical studies with neuroscience, because I thought this was fascinating, and since during my MD I got especially interested in psychiatry.

My PhD neuroscience was with Dr Charles Nemeroff at Emory University (GA, USA). The topic was to investigate mechanisms of action of antipsychotic drugs. It was about the possibility that certain neuropeptides, such as neurotensin, would be critical in mediating effects at least in some of the antipsychotic drugs. I used a number of different animal experiments in blocking neurotensin action, to show that its actions are essential at least for some of the behavioural read-outs that we have in animals with antipsychotic drug action.

You contributed to the recent Lancet publication on the priority problems in psychiatry.^1,2 What, from the perspective of psychiatric genetics and mood disorders, are the priority issues that should be guiding research over the coming years?
What cut across this number of short articles was that we need to move towards an understanding of mechanisms, and that this will lead to a recategorisation of disease. So we are moving away from symptom-based diagnosis towards mechanism-based diagnosis – on a circuit level, on the cell level, and on the molecular level – and the importance to tie all of this together.

We know, for example, that in some types of diabetes there is an autoimmune response against certain cells in the pancreas. We understand what is going on, and we understand all of the consequences. These consequences can be extremely diverse, depending also on when in the disease course you look.

We need to move towards this level of mechanistic understanding of disease in psychiatry. Now, the time is starting to be ripe with all of the new possibilities in imaging, the -omics approaches, and novel animal models. Also, with the possibility of using pluripotent stem cells, this is one avenue that could be hopeful and has shown some promise already. These are really exciting times in psychiatry.

Your work focuses on risk and resilience in responses to stress, such as childhood trauma. How do environmental stressors acting upon an individual translate into the maladaptive pathophysiology that we see in a number of disorders?
Our idea (and that of others) is that the environment can leave long-lasting marks on cells via diverse mechanisms. One – and this also counts for childhood trauma – is the direct activation of certain neural circuits. The activation of certain neurons leads directly to epigenetic changes. As we know, for example, during fear conditioning in animals, neurons are not only changing their firing pattern but are also changing epigenetically. So when they are stimulated again, they will also respond differently on a molecular level.

The other layer that we focus very much upon is that early trauma not only initiates direct responses on certain nerve cells, but that it also activates the stress hormone system. The stress hormone system actually has pervasive effects throughout the whole body. It binds to certain elements in the DNA – the so-called glucocorticoid response elements – and there very locally it can lead to long-lasting epigenetic changes. The change in response can be different in different tissues, but it can change the way the individual then responds to future stress. We think that this has to do with risk and resilience to psychiatric disorders.

Are there any mechanisms you can highlight in particular?
We are focussing on one gene that is an important regulator of the stress response, FKBP5^3,4. It is highly responsive to stress, and it has a feedback regulation on the stress system. So if it works too much, you actually have a prolonged cortisol response.

We know that there is an interaction between a genetic predisposition and environmental impact (such as early-life adversity), that will lead to a combined genetic and epigenetic dysregulation of this gene. The genetic variant will predispose an individual to make more of this gene when stressed, and this will impair their feedback downregulation of the stress response system. So they will have prolonged cortisol responses with every stressor.

When the stress happens early during childhood, and it is a strong stressor like abuse or maltreatment, there will actually be an overshoot in cortisol response in individuals with specific FKBP5 gene variants that will also have epigenetic impact on this FKBP5 gene, and will further disinhibit it. You end up with a genetically- and epigenetically-disinhibited FKBP5 response to stress.

We think that this predisposes individuals to be at risk of a number of psychiatric disorders, by dysregulating the stress hormone response into adulthood, but also by the direct effects of this gene.

We know that if you carry a certain risk variant in FKBP5, the high response variant, and you are exposed to childhood trauma, you are at higher risk for major depression, PTSD and psychosis. There is also a tie-in with substance abuse. It seems to be related to a more pervasive increase in risk for psychiatric disorders. This has now been shown in a large number of studies, including over 14,000 individuals if you put them all together.

You have spoken about the timing of stress exposure affecting the course of the development of maladaptive stress response, as well as inter-generational effects.⁵ When we are dealing with such dynamic interactions, how do you tease these effects apart so long after a traumatic event?
This is of course extremely difficult, and I would say almost impossible in humans. In humans, we can only get clues. Now, there are more and more studies in children where we see the trauma effects, i.e. the epigenetic regulations. What we are still missing is longitudinal investigation to really understand when the epigenetic changes start, and how it is carried on into adulthood. For example, what are the factors that determine this, other than the genetic predisposition? I know of a number of longitudinal studies that are investigating that now.

What we also do is use cell models, for example, and of course animal models. Cell models may be able to mimic early stages of development, such as during pregnancy. We see that treating cells early on with glucocorticoids will leave very long-lasting epigenetic marks in exactly the candidate regions that have been associated with a number of psychiatric disorders, e.g. schizophrenia and depression. But there are also some critical genes that are important for neural developments.

What are the current and future focuses of your lab?
One main focus is to understand how genetic predisposition (either through risk or resilience) interacts on a molecular level with stress exposure to have a long-term impact on the epigenetic timing of cells, and how that translates in different instances to activation when you are exposed to a stress test, for example. This will bring a better understanding of the interplay between genes, the environment, and the epigenome. It will give us some clues to getting some biomarkers for the individuals at risk, and identify targets that could be interesting potential drug targets.

For FKBP5, for example, we know that there is this disinhibition that seems to predispose us to psychiatric disorders. A colleague of mine here at the Institute, Felix Hausch, has developed a small molecule antagonist against FKBP5. This is showing, in animal experiment, the effects that we would hope for: blocking the effect of FKBP5, promoting stress coping, and reducing anxiety in these animals.

We are looking on a genome-wide level to explore the interplay between genetic variation, epigenetic variation and an environmental stimulus such as stress hormone exposure. We do that in humans, but also in different cell lines. One exciting area that we are moving into is pluripotent stem cells. We want to preselect for extremes in resilience or extremes in risk genes, especially for these stress-related genetic variants. Then we want to explore what happens when we take cells from individuals that are extremely resilient or extremely vulnerable to stress on their genetic profile. We expose these cells to stress hormones at different stages of cell development and neural development. Then, we are moving to the brain organoid to better understand how these things relate to the development of neural structures and connectivity.

Dr Binder, a member of the Executive Committee of ECNP, will present a plenary lecture at this year’s ECNP Congress in Vienna, in which she will detail her work in understanding the role of stress and adverse life events in mood and anxiety disorders.

References:
1. Stephan KE et al. Charting the landscape of priority problems in psychiatry, part 1: classification and diagnosis. Lancet Psychiatry. 2016 Jan;3(1):77-83.
2. Stephan KE et al. Charting the landscape of priority problems in psychiatry, part 2: pathogenesis and aetiology. Lancet Psychiatry. 2016 Jan;3(1):84-90.
3. Zannas AS et al. Gene-Stress-Epigenetic Regulation of FKBP5: Clinical and Translational Implications. Neuropsychopharmacology. 2016 Jan;41(1):261-74.
4. Binder E et al. Association of FKBP5 Polymorphisms and Childhood Abuse With Risk of Posttraumatic Stress Disorder Symptoms in Adults. JAMA. 2008;299(11):1291-1305.
5. Yehuda R et al. Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation. Biol Psychiatry. 2015 Aug 12.