Christopher Lowry, a Neuroendocrinologist at CU Boulder talks about a potential stress vaccine and how that could benefit high risk individuals.
Interview conducted by Ivanhoe Broadcast News in September 2019.
We’re here to do a story about something they’re calling a stress vaccine. How can you give a vaccine on an emotion?
LOWRY: So, essentially one part of the stress response is linked to how our immune system responds. And evidence suggests that inappropriate immune activation – in other words, excessive amounts of inflammation in response to stress – can have negative outcomes. And that includes increased risk of psychiatric disorders like major depression or posttraumatic stress disorder.
How is inflammation and stress linked?
LOWRY: Historically when we thought about stress, we thought about our hormonal response to stress, the autonomic nervous system response to stress. In other words, the fight or flight response. But it’s become clear in the last decade or so that in addition to those responses, the response of our immune system is also very important and has important impacts on how the stress affects our bodies.
And what is it in the immune system that affects stress?
LOWRY: One thing that happens during a stress response is the immune cells mobilize throughout the body and within the blood distributed throughout the body. These cells also release molecules called cytokines that can drive inflammatory responses and affect our physiology. And if those pro inflammatory molecules are released in excessive amounts, then we see negative outcomes.
And does that happen? Okay, let’s say in what type? Like PTSD? Trauma? Stressed out over work? I mean does that happen in every level of stress?
LOWRY: We used to associate activation of the immune system with tissue injury, being injured. You know, historically throughout human evolution being attacked by a predator, having a potent immune response in order to fight infection is really adaptive. But nowadays in our urban lives, it’s very rare that we actually face physical danger, trauma, tissue injury. Instead most of our stresses are psychosocial in origin, so giving a public talk is a very stressful event, for example, but very unlikely to result in bodily damage. However, we have a very strong immune response to this type of stressor. And individuals that have a diagnosis of major depression for example respond with a much greater activation of this inflammatory response than healthy individuals. And we think that this exaggerated response is part of the mechanism through which exaggerated inflammation increases risk for psychiatric disorders like depression and PTSD.
Are there any other impacts that stress has on the body?
LOWRY: Stress has many impacts on the body, not just through the immune system but also our hormonal system, what’s called the hypothalamic-pituitary-adrenal axis – the stress hormone axis – and also our autonomic nervous system, the sympathetic nervous system or the fight or flight response. All of these systems are really designed and optimized to enhance our ability to engage in fight or flight type behaviors, to defend ourselves against attack or injury. And after injury also to recover from infection, for example. But those systems are still activated today when we face these psychosocial stressors. And that may be because historically or evolutionarily, if you were experiencing a psychosocial stressor or conflict with someone in your tribe or another tribe, then that might also have a good opportunity for tissue damage and the need to fight infection.
So your stress vaccine is based on something that you find basically everywhere?
LOWRY: We’re working with a strain of soil-derived bacteria that was isolated in the early 1970s by John Stanford and his colleagues. He was an immunologist at UCL in London. They realized that vaccination programs against leprosy varied dramatically in their success based on geography. So, there were some geographical areas where these vaccines worked really well. So, they went to one of those areas around Lake Kyoga, Uganda, anticipating that there might be some environmental factor that could explain why these vaccines were so successful there. And they discovered this strain of bacterium called Mycobacterium vaccae. And subsequently they learned this. Injections of this bacteria can modulate our immune system in a way that prevents inappropriate inflammation, in addition to its apparent effect acting as an adjuvant to boost the efficacy of the vaccines that were being used.
And I was reading something about you, and it comes to an old theory, right?
LOWRY: The old friends hypothesis. This hypothesis has its origins in what’s called the hygiene hypothesis. That was put forward by David Strachan, again, a British scientist around 1990. And he observed that if you had older siblings you had much lower risk of allergic asthma. And he thought at the time that this was because you’re more likely to get more infections when your older siblings come home and transmit these infections. However, it’s become clear over time that it’s not just infections that can confer this type of benefit. It’s also our gut microbiome that plays a role. And Graham Rook noticed that environmental bacteria, in other words bacteria that are found in the soil, the dust, the mud, decaying vegetable matter – these environmental bacteria also can confer this protective effect of preventing inappropriate inflammation. So he refers to microorganisms that have this ability to limit our inflammatory response as old friends.
You’re going to be a less stressed adult if you play in the mud as a kid?
LOWRY: Exactly. There is evidence to suggest that that’s the case. We conducted a study with our collaborator, Stefan Reber, at University of Ulm in Bavaria, in Germany. And it was really designed to test this hygiene or old friends hypothesis in the context of psychiatric disorders. So young men that were aged on average twenty-four years old that either grew up in a city with over 100000 thousand people, didn’t have pets, or young men that grew up on farms with farm animals. And this was for the first 15 years of their lives. They were brought into the lab and exposed to this psychosocial stressor where they are asked to give a speech in front of a panel of scientists, and to conduct some mathematical tasks that are quite challenging. It’s very stressful. And the individuals that grew up on farms – they reported feeling more stressed, and feeling more anxious, but the individuals that grew up in the city had a massively exaggerated immune response to this psychosocial stressor, much like we would see in someone that has depression, for example.
If you grew up in the city, you grew up with more expectations, more pressure, more things to do. You grew up on the farm, less pressure, more family involvement, more relaxed. Is it anything do with that as well?
LOWRY: Those factors may well play a role. And other groups have certainly put forward those ideas, but it’s hard to explain why individuals that grew up on farms would feel more anxious, feel more stressed, have higher levels of stress hormones, yet have a lower inflammatory response. What’s really controlling that inflammation? Because we are not conscious of our inflammatory response to stress. It’s not like you give a public talk and you think oh my god I had such a massive inflammatory response. You know, you never know because we can’t detect that consciously. But it’s a silent response. We’re not aware of it.
Is it only special soil? Is it soil everywhere? Is it the soil in Uganda and Africa?
LOWRY: So that’s a great question. We showed in 2007 that injecting this particular strain of bacterium could have antidepressant effects in mice – activate serotonin neurons in the brain and increase serotonin metabolism in parts of the brain that are involved in depression in humans. And at the time, we were quite reluctant to suggest that exposure to soil just in general could have beneficial effects. However, since that time, since 2007, several studies have come out to suggest that simply exposure to soils may have dramatic health benefits. And the first was a study that was done comparing Amish children to Hutterite children. And so they come from similar backgrounds in Europe. However, the Amish have maintained traditional farming practices. They still use animals to plow the fields, for example, whereas Hutterite farmers now use industrial farming practices, including use of tractors. They were able to replicate that the Amish children have very low levels of allergic asthma. The Hutterite children have higher levels and on average children across the United States have even higher levels of allergic asthma, so non-farmers typically. And this group was able to take the soil or the dust from the homes of the Amish children, and that dust alone was sufficient to suppress allergic airway inflammation in mice. And they show that that dust is interacting with the immune cells that are in control of the innate immune response in the mice.
There was a study out just this year that said just walking barefoot in the park raises your happiness, all your hormones and things like that. So that kind of goes with the whole theory, right?
LOWRY: It’s difficult to tease apart what aspects of that experience are conferring the health benefits. I think there’s no question now that what has been called nature prescriptions or nature therapy can have health benefits. We just don’t understand all the mechanisms that are involved in those health benefits. But certainly just exposure to nature is beneficial.
How did your study work? How’s your study working?
LOWRY: We’ve done a number of studies and one of the most important studies was a study where we immunized with this bacterium in mice. These mice were exposed to a dominant male that formed a dominance hierarchy in their cage, and the mice that are subordinate – they respond with spontaneous colitis. In other words, inflammation of the colon. They have exaggerated chemically induced colitis in a model of inflammatory bowel disease. And they had increased anxiety. However when we immunized the mice prior to the stressor all of those outcomes of the model were prevented. And so this suggested that if you can immunize and prevent inappropriate inflammation then you can prevent a lot of negative outcomes of future stressors.
You talked about this for stress, but then could that have an impact on inflammatory diseases and colitis and IBD and all these problems and all that?
LOWRY: Absolutely and in fact there is a very close association between stress-related psychiatric disorders and autoimmune disease, for example. And so we know that individuals with a diagnosis of PTSD have a much higher risk of going on to develop autoimmune disease compared to individuals with a diagnosis of major depression or certainly compared to healthy controls. And so that might suggest that there’s simply an inability to control inappropriate inflammation, both in the context of stress exposure trauma and also in the context of preventing immune responses to self antigens, like what you see in autoimmune disease.
What’s next for your study?
LOWRY: We’re exploring alternative ways of administering these bacteria. So we just published a paper with Stefan Reber again showing that providing these mycobacteria intranasally, so in the nose, can have stress protective effects. And that might lead to a nasal spray for example. We also want to explore using these types of bacteria orally. So is it possible to take a pill and still get the same health benefits compared to injections? And then ultimately we’d like to move these studies into human populations to conduct clinical studies and clinical trials.
How do you see it working? You get one vaccine in your whole life?
LOWRY: There’s a couple of ways that we might approach this. One would be early life exposure because early life exposure to mycobacteria during development may have protective effects throughout life because of the developmental trajectory. During adulthood, it seems to be the case that repeated exposures are required. So we would envision that injections would only be given in high risk individuals that are at high risk of exposure to trauma. And we’re hoping that oral administration might be effective in a population level to inhibit inappropriate inflammation and risk not only of overt inflammatory disease but also these psychiatric disorders.
Considering your job, it might make you a candidate for this vaccine.
LOWRY: Yeah. There was an interesting study that was done several years ago at Whitehall in London. And this was a study of civil service personnel that work for the government and they knew for some time that the people at the very top of the hierarchy of Whitehall have very low risk of, say, developing cardiovascular disease. However, if you’re just one level down in the hierarchy, you have a higher risk of cardiovascular disease. And if you’re two levels down, it’s higher still. And so even in humans in the workplace, the social hierarchy makes a difference and people that are lower on the social hierarchy are at higher risk of these conditions that we know are in part mediated by inappropriate information like cardiovascular disease. They did a study in the same population and showed that If you just measure these proinflammatory biomarkers at baseline, those biomarkers of inflammation could predict depressive symptoms eleven years later. And so it’s that kind of chronic life exposure to inflammation that really puts individuals at risk, we think.
What is your hope for this? Is there is any risk for this?
LOWRY: With the injections, there’s a local immune response and there may be some localized inflammation. The clinical studies that have been done with that particular strain have a very good safety profile, so injection seemed to be tolerated very well by different patient populations. So I think the next steps for us because we’re interested in psychiatry are looking at individuals with a diagnosis of PTSD or major depression and seeing if we can improve stress resilience in these populations or even decrease symptoms of PTSD or depression. We’ve done a couple of studies in a model of fear-potentiated startle. And humans with PTSD show enhanced fear-potentiated startled. So when you’re afraid, say in a dark alley, and you hear a loud noise your startle response is much greater. And we go through a process of extinction where fear memories are extinguished over time when we’re in a safe environment. However, in these studies we were able to show that if we immunized with the bacteria prior to fear conditioning, then we can enhance the rate of fear extinction. Maybe the most exciting finding is if we immunize after the fear conditioning, it also enhances fear extinction. So this is really exciting because it suggests that it could lead to let’s say a “day after” intervention following trauma, for those at risk of developing PTSD. And this might be an opportunity to intervene after trauma and prevent development of PTSD.
That’s really exciting. Anything else?
LOWRY: There is another application that we think is very interesting, and one thing that we haven’t mentioned is not only does the immunization prevent inflammation in the body, but it prevents inflammation in the brain. In fact, just injecting the bacteria – and we don’t really understand how it does this, but injecting the bacteria shifts the brain toward an anti-inflammatory phenotype. And so even without stress exposure, the brain shifts toward an anti-inflammatory phenotype. And subsequently, the brain is protected from stress-induced neuroinflammation or microglial priming. So the immune cells in the brain can become primed by either stress or aging, so the natural process of aging. And then when these cells in the brain become activated in the future, they overreact. And so the immunizations were able to prevent that priming process and the exaggerated neuroinflammation.
What type of illness does that protect from?
LOWRY: We think that may be important in psychiatric disorders – stress related psychiatric disorders like depression and PTSD. We also think there may be applications in something called post-operative cognitive dysfunction. We know for example that individuals that are over the age of 60 have a high risk of developing cognitive impairment after surgery. So simply being older puts you at risk of developing this cognitive impairment. And we have a model of this in our preclinical animal studies. And we show that surgery impairs cognitive function measured three days after surgery. However, the immunization with the bacteria prevented both the priming of the immune cells in the brain and prevented the cognitive impairment. So here you have a situation where there’s an at-risk population – in other words, individuals over 60 – that know they’re going to have surgery. There is a high risk, maybe 40 percent of those individuals, that will go on to develop serious cognitive impairment, and here’s an opportunity to immunize and prevent that cognitive impairment after surgery.
For kids who live in New York City or somebody who works 60 hours and commutes into the big city, could this be a once or twice a year vaccine where it doesn’t have to be an extreme case?
LOWRY: It’s more likely to be once a month as opposed to once a year. That’s because the cells that are being induced by the immunization are called regulatory T cells. It’s part of our immune system that is designed to keep inflammation under control, to release anti-inflammatory cytokines. And those cells, once they’re induced, they have a finite half-life. And so they’re induced, they can do their thing, but they don’t last forever. They need to be replaced. However, if this approach works orally, then it might be the case that you have simply a stress resilience, or wellness opportunity to promote stress resilience and promote well-being for those types of individuals. A nutritional supplement.
END OF INTERVIEW
This information is intended for additional research purposes only. It is not to be used as a prescription or advice from Ivanhoe Broadcast News, Inc. or any medical professional interviewed. Ivanhoe Broadcast News, Inc. assumes no responsibility for the depth or accuracy of physician statements. Procedures or medicines apply to different people and medical factors; always consult your physician on medical matters.
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