Unravelling the causal links connecting mind and molecules

Ever since the Age of Enlightenment, science has lived on the premise that our body is made up of separate compartments, each organ with its own function, purpose and treatment. Even today, people see a cardiologist for heart conditions and defective blood vessels, a hepatologist for liver issues, and a neurologist or psychologist on matters of the brain. This compartmental view and professional specialisation does have its limitations. Psychologists, for example, master the behavioural aspects of the mind but know little about the molecules that drive that behaviour. Our thrift to deliver highly specialised professionals has resulted in little understanding of organ-organ interactions and how molecules formed and released by the body affect the brain, and vice versa. For the past four years, TNO has been conducting pioneering research that unmasks previously hidden correlations between mind and matter.

The Body Brain Interactions ERP looks at connecting and interrogating the mechanisms that make our body and brain interact. The ultimate aim is to fully understand how stressors that target our brain affect our body and our health, and contrarily how the molecules in our body influence our mental well-being and cognitive performance.

Now in its fourth and final year, the TNO researchers have achieved a feat that is unique in the world: identifying main causal links between our body and our brain. Interactions that previously went unnoticed, or could not be studied because the technology simply didn’t exist.

Already attracting worldwide interest

Some studies within the ERP have made such headway that they have been peer-reviewed and published in renowned scientific journals, igniting interest among commercial and governmental parties to collaborate with TNO. One of those studies, which was published in Nature, demonstrates that we have long neural conduits that run from the brain to the tertiary lymphoid organs (extremely small lymph nodes) in all blood vessels of our body. This proves that these nerves are activated by chronic stress sensed by our body.

It is important to realise that our body is a much more objective sensor of chronic stress than our mind. After all, the human brain can misleadingly see stress as a show of high tolerance, strength, or even bravura. In other words, when your body senses stress (even if you aren’t feeling stressed), it activates the autonomic nervous system, after which the nerves trigger the immune cells in tiny lymph nodes. These immune cells are responsible for chronic inflammation in your body, the main driver of many potentially fatal diseases including cardiovascular diseases, heart failure, and promote diabetes and many cancers. TNO researchers showed in Neurology (Vreeken et al 2022) that similar body-brain interactions exist between our fat depots and the brain. This attained knowledge presents new insights into how we can interfere with and reduce the impact of chronic stress, and thus attenuate the development of disease.

Another fascinating private-public partnership that has emerged from the ERP’s first years of research is with the Dutch Digestive Foundation (Maag Lever Darmstichting or MLDS). Together with TNO, the MLDS wants to learn which signals the body transmits to the brain that make you feel pain, for instance gastrointestinal pain that is often misunderstood and thus not properly treated because doctors are unable to find a cause. The TNO researchers have discovered that molecules formed by the liver and the gut microbiota together characterise patients with complaints, providing an entirely new rationale and target for treatment.

The research of Body Brain Interactions also focuses on inflammatory molecules, or cytokines, which are released by our organs and act as an alert signal to protect the body from bacterial and viral invasions. But when these molecules are chronically released, all kinds of health threats can occur. Especially in highly overweight individuals, the study shows that the chronic release of cytokines from visceral fat (the fat that surrounds organs and the gut) is detrimental to the brain perfusion, oxygenation and glucose level in the brain cells, a condition that causes neuronal death. Depending on the affected brain region, it is a clear trajectory to dementia, Alzheimer’s disease and Parkinson’s disease. Interestingly, preliminary research data indicate that the very same cytokines play a role in cognitive performance decline after acute stressors such as sleep deprivation. This is highly relevant for shift workers, people in the military and others in high-stress professions.

From understanding interactions to applying intervention strategies

As exciting as the results from the Body Brain Interactions ERP are, there is still a long way to go on the road to implementing the acquired knowledge. We now know without a doubt that the body and brain interact, and we understand more about the molecular interactions. What we still need, however, are intervention tools. Moreover, the causalities are much more complex or obscure than in the examples above, or simply haven’t yet been detected.

“We have scratched the surface of fundamentally novel ways to prevent and treat chronic-inflammatory metabolic diseases”, says principal scientist Dr Robert Kleemann of the Healthy Living and Work unit. Prof. Jan van Erp, principal scientist of TNO’s Defence, Safety and Security unit, adds: “And the same interactions can be used to augment health, stimulate resilience and potentially improve cognitive performance, which is key in stressful jobs or during military missions”. The scientists agree it is a clear win/win for both units.

The next step is very challenging and requires even greater collaboration to find intervention strategies for certain interactions. It is essential that these interventions beneficially affect multiple organs simultaneously, including the brain.

Such a holistic approach will literally save lives, Dr Kleemann believes. “We’ve already come so far in learning how our body and brain interact. It is time to focus on building biological shields that help protect our physical and mental health. Think of the impact which ‘behavioural shields’ could have in reducing stress and calming our minds, for example, but also building protective ‘biological armour’ through optimizing our microbiota, stimulating muscle health, or by improving energy supply via the liver.”

By strengthening biological shield mechanisms, we can cushion the chronic stressors first, so that acute stressors are less detrimental to our health. We need to accept that we are all exposed to stressors, whether chronic or acute. The trick now is to manage those stressors effectively. Despite the difficulties of changing people’s behavioural ways, both principal scientists are confident that the combination with biological protective shields will have significant benefits for our health, mental well-being and performance.

The Body Brain Interactions ERP is a collaborative research programme of the TNO units Healthy Living and Work and Defence, Safety & Security. If you are interested in working with TNO, please contact Dr Robert Kleemann or Prof. Jan van Erp.