Interviewer: Examining the latest research and telling you about the latest breakthroughs, The Science and Research Show is on The Scope. Who your parents are matter. Dr. Christopher Gregg, a professor in neurobiology and anatomy, is researching patterns of inheritance that long-term effects on behavior and the development of mental health disorders. Dr. Gregg, what motivates your work?
Dr. Christopher Gregg: The cost of mental health in society, mental health issues, are unbelievable. Unbelievable. Most of the people in prisons, most of the people that are homeless, most of the people that are struggling to get by in life are suffering from some mental health issue.
Addiction, all of these problems are brain related and behavior related. At the moment, most of the pharmaceutical companies are pulling money out because the brain is so hard to figure out. It's so hard to find targets and it's so hard to find effective ways to influence behaviors in a predicable manner.
So in my mind, I think because we think we are able to decode these pathways in the brain, I think we have a very unique place in the field. I think we have a real opportunity to make a difference.
Interviewer: You're interested in how behavior is inherited?
Dr. Christopher Gregg: When people think about behavior I think they think a lot about the factors in their environment. So you might think about what role your parents played in your upbringing, what are your socioeconomic circumstances, what sorts of stresses and pressures do you have in your life, and so you think about the behaviors that you have or maybe why a particular disorder or addiction or some stress or anxiety disorder might emerge and you might think about those issues.
But, in fact, it looks like most psychiatric disorders are strongly influenced by your genes. So as a consequence, we have focused an enormous amount of effort in our research program in trying to define the genes that influence specific behaviors.
Interviewer: So why is that interesting to you?
Dr. Christopher Gregg: We had known before that there were these rare examples of genes called imprinted genes that exclusively express the copy you get from your father or exclusively express the copy you get from your mother, but people didn't have any way to study them in a kind of unbiased manner. So we set about to find all of these imprinting effects in the genome.
The bigger vision continues to be a general interest in finding antagonistic pathways in the brain. So when you think about many behaviors or different physiological states, they're opposing. You can be hungry or you can be satiated. You can be anxious or you can be calm. You can be social or you can be antisocial.
Naively, we thought maybe we could kind of decode the genome into the genes that push you down one path versus the genes that push you down the other path.
Interviewer: Why did you look into that in the first place?
Dr. Christopher Gregg: There was a theory proposed several years ago by an evolutionary biologist named David Higg. David proposed that there would be a conflict between mothers and fathers in placental mammals. The reason was that mothers are the only ones that make a metabolic investment by supplying nutrients through the placenta or through the nursing through lactation and fathers don't make any investment.
David predicted that mothers would evolve mechanisms that make the offspring less demanding and fathers would evolve mechanisms that make the offspring more demanding so they grow bigger, consume more resources, and outcompete the offspring for mother and father.
Interviewer: So how do you think how genes are expressed in the brain might fit Higg's hypothesis?
Dr. Christopher Gregg: We think the weaning period is sort of a major point of conflict because this is the period when offspring develop behavioral traits that are required for them to be independent from the mother. They become independent in terms of being able to find their own food. They have changes to anxiety and exploratory behaviors, changes to learning and cognition. Those changes have a major impact on the mother. The faster and more effectively that the offspring transition to being independent the less the demand on the mother's resources.
Interviewer: A lot of your work focuses on genes that regulate brain function or behavior and whether they're inherited from your mother or your father.
Dr. Christopher Gregg: The researchers in my lab have spent time developing technologies that allow us to study the expression of genes you get from your mother and compare them to the expressions of genes you get from your father. We find there are a lot of really interesting differences.
What's particularly compelling about some of those differences is that they seem to be particularly enriched in the brain. So we looked at differences in the expression of genes from maternally and paternally inherited chromosomes in the liver, in the muscle, and now in two brain regions, and in the developing brain and we find there are a lot of differences in the developing brain and in the adult brain but not very many differences in the liver and in the muscle. The chromosomes you get from your mother and the chromosomes you get from your father are used differently in the brain.
Interviewer: Were you surprised to find that? Did you actually think it would turn out that way?
Dr. Christopher Gregg: We were very surprised. We continue to be surprise as we discover more and more things as we're doing this work. Now what I think is important to recognize is the implications of our study for human disease are that if you inherit mutations from your mother versus your father in these genes, it will have different effects on you.
Imagine you did a mutation in a particular gene that's imprinted and you inherent that mutation from your father. If you don't express the copy that you get from your father because there's a bias to express to copy that you get from your mother because it's a maternally expressed imprinting, then that mutation is not going to have such a deleterious effect on you. On the other hand, if you inherited that same mutation from your mother for that gene, then the effect is expected to be much stronger because there's no other healthy copy to buffer the effect.
Interviewer: So the idea is that one day, if you find that a susceptibility to being autistic is more likely to come from your mother, then the healthcare system can come up with a way to test for that?
Dr. Christopher Gregg: We already are able to analyze the genome sequence of a patient and we're able to analyze a genome sequence of that patient's parents. We can determine whether a mutation has been inherited from a mother or a father and by looking at that mutation, as well as many other mutations in an individual's genome, we think that we'll be able to infer whether that person is at risk for developing psychiatric disorders at later stages in life.
Interviewer: Are there some genes that you found that might suggest this antagonistic control, where one side has the opposite function of the other and that might be connected to a behavior?
Dr. Christopher Gregg: In very preliminary work we think we have defined antagonistic gene pathways that regulate anxiety and maybe risk for panic disorders.
Interviewer: So what's the next step to take that work?
Dr. Christopher Gregg: I think we have a very clear path ahead of use. We're going to define these pathways that are antagonistic and make you less or more anxious, for example. Then we have developed software in the lab that builds on those insights to find how those pathways intersect with known drugged pathways and our goal is to develop novel therapeutics and novel therapeutic strategies by leveraging that insight.
Then on the diagnostic side, by finding novel pathways that influence anxiety we can more accurately identify individuals that are at risk for developing an anxiety disorder.
The greater vision of the work in the lab is to define all of the sort of these functionally antagonistic pathways in the brain that drive different aspects of behavior and to develop a panel of markers that will help diagnose susceptibility for aberrant motivated behaviors and to develop novel therapeutics that modulate these pathways so that you can treat people that have problems with addiction, anxiety, social behaviors, eating disorders, these types of things.
Interviewer: Interesting, informative, and all in the name of better health. This is The Scope Health Sciences Radio.
