AEN Profile: Professor Gerlinde Metz. Transgenerational Epigenetic Programing of the Brain Biography: Dr. Gerlinde Metz is a Professor of Neuroscience and AHFMR Senior Scholar at the Canadian Centre for Behavioural Neuroscience at the University of Lethbridge, Alberta, Canada. Dr. Metz completed her undergraduate studies in biology at the University of Giessen, Germany, and graduate studies in neuroscience at the ETH Zurich, Switzerland. She habilitated in medicine at the University of Jena in Germany. Using innovative behavioural, physiological, morphological, molecular, and genetic analysis, Dr. Gerlinde Metz investigates the influence of experience and environment on behaviour and brain plasticity. Her work was the first to show that stress affects motor function and diseases of the motor system, such as Parkinson s disease. Dr. Metz s research has demonstrated that, through epigenetic changes, adverse experiences at any time in life can be a predisposing or precipitating factor of disease. Furthermore, Dr. Metz and her team have shown that through transgenerational epigenetic programming, stress can influence lifetime health and disease trajectories of future generations. Dr. Metz s laboratory has developed a rat model of transgenerational prenatal stress. This model allows the study of transgenerational inheritance of health and disease, such as the risk of preterm birth, and associated epigenetic signatures. She hopes that the understanding of disease origins through transgenerational studies may open new avenues for disease prediction and intervention. Q. Why did you decide to focus on behavioral neuroscience? I have always been fascinated by animal behavior. When I was in high school I raised chickens as pets. These chickens would imprint on me and follow me everywhere. They would spend a
great deal of time in the house and felt comfortable laying their eggs in my bed. One of them became a celebrity on a theatre stage. This experience strengthened my already-strong interest in animal behavior and led me to study biology in Giessen and neurosciences in Zurich. Also, I find the incredible complexity of our brains fascinating. Q. What brought you to the University of Lethbridge? I was drawn to Lethbridge by the Canadian Centre for Behavioural Neuroscience. When I finished my training in Switzerland and Germany I looked for positions at institutions with a strong behavioral neurosciences program that possessed good facilities and good infrastructure. The Canadian Centre for Behavioural Neuroscience was the only institution that really fit my requirements. It is an incubator for behavioral neurosciences, with 16 co-located interdisciplinary principle investors that share equipment, infrastructure, and students. Q. What are your thoughts on the somewhat controversial mega-scale brain projects (EU- The Human Brain Project and USA- BRAIN Initiative)? These projects are a significant investment into brain research. Some claim that is too early and we don t know enough about the fundamentals of how the brain works to make meaningful progress in these large projects. Others are worried that too much money is going to too few labs and important centers and individuals are being excluded. However, I think overall, that these are positive initiatives to draw attention to the urgent need for funding in basic science and brain research. The brain is extraordinarily complex and requires a large-scale multidisciplinary approach that investigates the brain at multiple levels of resolution, from the molecular level to integrated system levels. Large multi-laboratory projects also help to standardize procedures and analysis methodologies. This is very important for reproducibility and for the translation of research to clinical applications. Epigenetic markers change over our lifespans, so simple things like collecting samples at the same time become very important. However, it is hard to standardize everything, even within laboratories. For example, it has been shown that mice can respond differently when tested by female versus male experimenters. Similarly, it is impossible to control for all variables when working with human subjects. This variation makes large sample sizes necessary but it is also important to look at subjects as individuals because individual differences can be important for treatment outcomes. Q. Why is epigenetics important in the neurosciences? The brain is highly influenced by the environment, and epigenetics is the ultimate interface between environment and the human body. We are finding that brain plasticity is programmed by experience. The Developmental Origins of Health and Disease (DOHaD) concept describes that environmental induced changes in development in early life have a long term impact on later health and disease. For example, studies by Drs. Moshe Szyf and Michael Meaney, have shown that the brains of rat pups raised in stressful environments (less maternal care) have changes in the epigenetic marks on genes that control stress response (glucocorticoid receptors). These pups exhibit altered behavioral responses to stress in later life.
Q. What brought epigenetics into your research? Around 15 years ago I started to investigate how experience could affect the recovery from brain injury and how early experiences influence health and disease trajectories in later life. Around this time there was a revolution in the understanding of epigenetics, driven by next-generation sequencing. Fortunately I was able to learn from and collaborate with Igor and Olga Kovalchuk, who were pioneering the field of epigenetics in Alberta. Q. What epigenetics methodologies do you utilize? In collaboration with the Southern Alberta Group for Epigenetic Studies (SAGES), we have used the Illumina platform for deep sequencing of mrna and mirna and bisulfite sequencing. In addition, we routinely use microarrays and in situ hybridization for localization experiments. Q. Although methylation (5-methylcytosine [5mC]) is the predominate epigenetic mark in most tissues, hydroxymethylation (5-hydroxymethylcytosine [5hmC]) is common in differentiate brain tissue. What is the role of 5hmC and why is it more common in brain tissue? The exact roles of methylation and hydroxymethylation are still being determined. The brain shows incredible plasticity throughout a lifetime and it is thought that these marks play a significant role in neuroplasticity. There is a 10-fold hydroxymethylation enrichment in neurons; unlike methylation, hydroxymethylation seems to promote transcriptional activity. As the brain ages there is a loss of both methylation and hydroxymethylation, potentially explaining the overall decrease in gene expression that has been reported. Therefore, methylation/ hydroxymethylation likely play an active role in development and aging processes. Q. Where will epigenetics have the biggest impact in neurosciences and brain health? The ability to use epigenetic markers (or proxies) as biomarkers to predict diseases will be a tremendous clinical tool. microrna can be quite stable and may be detectable in the blood, or alternately metabolomics could be used as a proxy of the epigenetic state and collected from hair or urine. Biomarkers like these could be used to diagnose a wide range of health issues, such as stress or depression. Q. Due to the epigenetic reprograming of gametes and fetuses, the idea of transgenerational epigenetic inheritance is still somewhat controversial. What is your assessment of the evidence for transgenerational epigenetic programing? I think there is very strong evidence for transgenerational epigenetic programing. In my lab we have established a rat model that is used to monitor epigenetic changes across generations. We are finding that the physiological effects caused by environmental stressors can be passed down transgenerationally through epigenetic mechanisms. Others have shown that male mice exposed to stress have significant changes in the microrna content of their brain tissue, a change that is related to altered behaviors. The laboratory of
Isabelle Mansuy in Zurich showed that some of the micrornas linked to stress were also overexpressed in the mice s sperm. It was observed that offspring of these mice inherited the altered behavior from their fathers. To demonstrate that a specific microrna was producing behavioral alterations in the offspring, this microrna was injected into mouse sperm. When the sperm with the injected microrna was used to produce offspring, the offspring also demonstrated the altered behavioral patterns. It is therefore probable that stressors cause changes in brain physiology that is passed on to the mouse sperm s microrna (and to the next generation) via endocrine programming. Q. How representative is the rat model for human epigenetics? What other models are used? Testing humans directly is practically and ethically challenging. It is typically not possible to obtain brain samples from living humans and so we cannot know if blood is always a good proxy for neural tissue. The human life span makes it difficult to conduct longitudinal, and especially transgerational, studies. Therefore, there are many different models used in neuroscience studies. Nematodes (roundworms) are used because their nervous system is relatively simple and has been completely mapped. Fruit flies are used because they have very rapid generation times. As mammals, rats are more closely related to humans than these other models, many of their stress responses, stress hormones, and micrornas are shared (conserved) with humans. Their relatively small size and relatively short life spans make it possible to monitor a meaningful number of test subjects for several generations. Furthermore, rats have complex social behavior and they allow scientists to conduct in-depth behavior analysis. No model is perfect, but the limitations on human test subjects make experimental models a necessity. Q. What rat behaviors do you use to test your theories? It is important to look at as many tests as possible and use a combination of different tests to look for behaviors and behavior changes that might mimic human responses. We use a water maze to test spatial learning. In this test rats are placed in a pool of water and are required to use visual cues in the environment to find a submerged (hidden) platform. To test for skilled movements, we have the rats reach for banana flavored food (which they love) though a small opening. This reaching movement resembles human hand movement and can model movement disorders. Q. What key epigenetic-related questions would you like to see answered in the next 5 10 years? First, I would like to see a greater recognition of the role epigenetics mechanisms play in health and disease, especially in neurological disorders. I would also like to have a better understanding of the relative contributions that methylation, histone modifications, and microrna have in disease states and which of these represent the best biomarkers and therapeutics.
Q. If you had unlimited time and resources, what scientific problem would you like to solve? Human populations are obtaining increasingly longer life spans. Unfortunately, the health of our bodies sometimes outlasts the health of our brains. If I had unlimited time, I would do extended longitudinal studies of human populations (and even transgenerational studies) to investigate how life span and health trajectories change over time and the impact that epigenetics has on these changes. It is already known that total global methylation in the brain decreases over time, but it is unclear if this is a direct cause of aging and how experiences and life style interact with it. Ultimately, this research is important to understand how we can enhance the brain s chances for healthy aging to prevent diseases such as Alzheimer s and Parkinson s disease. Q. What can be done in Alberta to ensure researchers in Alberta are able to compete at an international level? Scientists in Alberta are generating fascinating epigenetics data and have valuable cohort studies. However, I feel that the total value in these datasets is greater than their single parts. To fully exploit their potential, an accessible platform to share all the data being generated, combined with the bioinformatics capacity to analyze it would be very powerful. Such a large-scale repository could contain omics data, phenotypic data, life style data, and health records. It would be ideal if this database was associated to a biobank that connected to the datasets with tissue samples. Combined with our established collaborative strengths across Alberta universities, this platform may help to attract more international spotlight. Q. What is the main value of having an Epigenetics Network to support researchers and Clinicians? There is an increasing need for a dialogue between basic researchers and clinicians. Researchers, like myself who are working with experimental models, need to collaborate with clinicians in order to make our research relevant for human health. Therefore, excellence in a field like epigenetics requires interdisciplinary teams. Investigators with diverse interests can find intersections and solve shared problems at the interface of epigenetic mechanisms. The Alberta Epigenetics Network is a critical framework to help facilitate such interdisciplinary discussions and programs. Q. When you are not in the working, what is your favorite pastime? If you could start over and pick any occupation, what would you chose? I am doing what I love. I find great inspiration and motivation to study the influence of early experiences on brain development by spending time with my daughter and from learning about my family s experiences in world war two in Germany. I find my job to be both very challenging and creative. In addition, having the opportunity to work in teams with basic and clinical scientists from different backgrounds and from around the world is very rewarding.