Edited by Lucile Bruce, Communications Officer at Connecticut Mental Health Center; and Shane Seger, Communications Officer at Yale School of Medicine's Department of Psychiatry.
On Friday, October 24th, 2014, Yale Department of Psychiatry hosted a tribute to the careers of Drs. George Aghajanian and George Heninger. Combined, the two have contributed more than a century of service to the department and to the Connecticut Mental Health Center. Over the last five decades they have made crucial discoveries that have advanced our understanding of and treatments for mental illness. Their mentees have become some of the most prominent leaders in psychiatry and neuroscience.
In advance of this event, Drs. Aghajanian and Heninger discussed their accomplishments, assessed the state of psychiatric research, and shared some advice for future trainees.
Looking back on your career, what are you most proud of?
Dr. George Heninger: Two things. Helping a large number of young psychiatrists blossom in their careers and become leaders in the field. And helping to get the department’s Division of Molecular Psychiatry started. The division’s research has allowed us to understand the mechanisms and action of psychiatric drugs at the cellular-molecular level, which has provided improved opportunities to discover new treatments, and most importantly, it has provided an improved understanding of the environmental and genetic-molecular factors that could be causing mental illness.
Dr. George Aghajanian: I would say that the first accomplishment—in the 1960s—was to be the first to record the single cell activity of the newly-discovered serotonergic, noradrenergic, and dopaminergic neurons in the brain. From there, we were able to study their intrinsic electrophysiological properties as well as the effects of neurotransmitters and drugs on their function. I didn’t have much company in that area for a few years and then I had a lot of company. Most recently, it would be the discovery that the rapid and prolonged antidepressant effects of ketamine resulted from the ability of a single dose of this drug to increase synaptic connectivity. Now, ketamine is a major focus in the research group and the field.
What got you interested in psychiatry and psychiatric research?
Heninger: I grew up on the grounds of the Utah State Mental Hospital. My dad was the superintendent. We were a quarter-mile from the hospital and you could hear people screaming. I didn’t know much about mental illness when I was a kid and I didn’t really care very much. I was just a regular kid. But in those days there was polio; my friends had polio, my dad had polio, FDR had polio. To me, the discovery of how to prevent polio with a vaccine was an example of what I wanted to achieve for mental illness. In high school I wrote a paper on antibiotics and it sort of struck me as a miracle that you could kill the germ without killing the person. That was just an earth-shaking development. And I still think so. That was the origin of the notion that, gee, maybe there is one for mental illness; maybe you can fix the molecules in the brain so people aren’t sick. That idea took me through medical school and the emergence of psychotropic drugs. I pursued this line of research because if we could understand the drug maybe we could understand mental illness. Things haven’t changed since I was in high school. We are still looking for our antibiotic.
Aghajanian: When I started medical school I was interested in research. And I’d been reading occasional articles about this drug LSD that could very rapidly alter mental activity. But the mechanism was unclear. So I chose that as the subject of my thesis. Specifically, I studied tolerance, which is the phenomenon of declining response to a drug with repeated doses. At the time LSD was not a controlled substance so any physician could write to the drug company that discovered it and receive ampules of LSD to use in whatever they wished. No protocols, nothing. Things were different in those days. After an internship elsewhere, I went into the Army and while I was there, my thesis advisor, Danny Friedman, got in touch with me and suggested I apply for a career scientist development award. I received a letter thanking me for applying. Things were very different then. I returned to Yale into the biological sciences training program. That’s how I got started, at the very beginning of the biological program in psychiatry. I didn’t intend to do clinical research myself because at the time I didn’t think one could get at the basic mechanisms so easily that way. But it was always my goal to see the translational implications of basic research. And that’s really been the whole philosophy of the program here since the beginning.
What is translational research? Why is it important? And what are the greatest challenges in doing it?
Aghajanian: What people mean by translational research is that if a biological mechanism is discovered, a discovery that seems to inform what might be going on with a disease, that we could apply that basic knowledge to conduct clinical studies with the goal of developing new treatments. Reverse translation is when a discovery is made in a clinical setting, to then go back and look at the basic science mechanisms that can explain it. Translational research has been happening in this department since the late 70's. Probably the first big translational finding here was the use of clonidine for opiate withdrawal. A basic finding was presented during our weekly biological science training program seminar, then another faculty member tested the finding in an animal model, and ultimately one of our grand rounds speakers tested the approach with patients. It worked. And the treatment is still being used today. There are difficulties on the basic side of the equation, because some of the drugs that are studied are controlled substances and it is difficult to get approval to use them. But I think the obstacles on the clinical side are even greater.
Heninger: Yes, the issue is access to specific compounds. The pre-clinical researchers have pretty much every chemical compound in the world at their fingertips. The issue for human use is safety. There are a number of compounds that could be tried in humans but investigators cannot afford it and the drug companies won’t help out. The companies are not interested in taking the risk of additional side effects being discovered. Today’s pharmacologic investigators are extremely limited.
CMHC was established with basic labs and a clinical research unit on the same floor, to create a structural advantage for translational research to occur. Was that successful?
Aghajanian: Yes, that was the original concept of Fritz Redlich, who was the chair of the Department of Psychiatry at the time. Redlich with others went to Governor Ribicoff and said, “I propose that there is a mental health facility in New Haven, and I propose that we incorporate into that mental health center a research unit.” And the governor and the legislature agreed.
Heninger: There are only two other places in the world that are constructed like the Connecticut Mental Health Center—National Institutes of Health and Columbia—where the basic laboratories are built in such proximity to the clinical unit. That was a fundamental structural design.
Was it exciting to be doing psychiatric research at a time when CMHC was so new?
Aghajanian: Yes, my lab was the first thing to open at CMHC, before patients were admitted. Being on the ground floor of such a unique project, I really felt a commitment to see that mission through.
Heninger: It was very exciting. I don’t know how to portray the excitement at the time without a two-hour movie. The enthusiasm was boiling over. CMHC opened right when the civil rights movement was starting and the hippies were there, and they were taking LSD in San Francisco. And there was a lot of social flexibility at that time. It was before Reaganomics.
Dr. Heninger, in 1997 you were quoted as saying that when CMHC opened, its research goals were “to cure everything, including race relations and poverty, and to prevent mental illness.” How do you see social and environmental factors relating to neuroscience research?
Aghajanian: I’ve got to say something about that. Just very briefly, that stress is one of the main risk factors, along with genetics, in mental illness. And poverty is very stressful. They are very linked.
Heninger: Some things cannot occur before their time. You don’t go to the moon in a wooden rocket ship. I mean, you have to wait until the pieces are ready. So the reason we haven’t cured mental illness in 50 years is that we don’t have our hands strongly on the causal factors.
Aghajanian: I think we know a great deal about the pathogenesis of psychiatric illness today.
Heninger: Well, we know about it, but we haven’t interrupted it.
Aghajanian: Oh yes we have. We can restore synapses. That is such a huge advance. In schizophrenia you have a loss of connectivity, a loss of synapses. And in major depression, in bipolar—all the major psychiatric disorders are synaptic degenerative disorders. When you restore synapses, it dramatically and rapidly normalizes people. That’s a really big opening.
Heninger: One of the ways you can maybe combine the two ideas is by the question of vulnerability, because the question was about poverty and stress. There’s a curve that I think pretty well demonstrates that with a little bit of stress, 10% of the people get post-traumatic stress disorder, and with a lot of stress, it can get it up to 100%. So you have an interaction between the resilience of the person and the manifestation of the illness.
Aghajanian: That’s become the focal point of the basic research—that very idea.
Are we at the point where our knowledge about the causes of stress can be used to reduce stress and its effects?
Aghajanian: Yes. Pathways have been found that trigger synaptogenesis. Exercise, for example, activates that pathway.
Heninger: What we will need to do is to identify those vulnerabilities in people ahead of time. Once we get the genetics and other factors out on the table, then we can tease out the interaction. It’s extremely difficult to do this when you don’t have the fundamental players. Some genetic vulnerabilities are very big Down syndrome, for example, will manifest in any environment. Other vulnerabilities are small. The next frontier is being able to understand the genetic vulnerabilities and adding them to the neuroscience and what we know about the physiology of the system.
Aghajanian: And George tells me that he regrets that he isn’t starting his career right now.
Heninger: My point is that if you are trying to get to the moon you need good rockets, something that withstands the forces. And if you put these two things together, then you can get there
You are both well known for mentorship. What advice would you have for a young person who is considering a career as a neurobiological researcher?
Heninger: My advice is to train really hard in genetics. That field is exploding so fast and it is so big that senior investigators like me can’t keep up. And then integrate those methods to figure out how the genetic vulnerability interacts with the environmental factors that cause a disease.
Aghajanian: As far as mentorship goes, I think the best policy is to see your students and postdocs as people that you want to help in their careers. They are also helping you, but you have to always bear that in mind that they are not just here as a labor force to further your own means. Their success is your success. As far as degrees go, I would say that getting an MD/PhD is ideal. It would be hard to focus on the basic side of translational research without an MD/PhD. And the other advantage is that MD/PhD students don’t wind up with a huge debt, which drives graduates into more lucrative clinical practice rather than research.
You are both medical doctors, psychiatrists, who had patients early in your careers. How did that experience inform your scientific work?
Aghajanian: Yes, certainly. Seeing patients gives you a special perspective on what it’s like to be mentally ill. And then it is important to always keep that in mind when thinking about the translational importance of any basic research.
Heninger: The most important thing for me is always my mother and father and living right behind the mental hospital. Then I got sick with rheumatoid arthritis when I was a freshman in college. It temporarily derailed my career. That personal experience with illness, versus seeing it from the outside, has stayed with me. The number one thing is recognizing the suffering and how big a problem it is. And number two, the variability of the illness. The DSM and all those schemes that people have to categorize mental illness, they impair our focus on the real issue. Our diagnoses are behavioral. They’re not precise. They throw people off the track of preventing and getting hold of the problem with real medicine. Let’s end that. Let’s get over it, like we do with infectious disease and other diseases.
Aghajanian: I think the state of psychiatry is not quite as backward as George thinks it is.
Heninger: Not as backward as it was. It is backward compared to infectious diseases.
Aghajanian: Well, you helped change that.
Heninger: So did you.