The science behind the strangest biological phenomena | David Linden: Full Interview

David Linden, a professor of neuroscience at Johns Hopkins University School of Medicine, discusses neuroplasticity and the profound connection between the mind and body. He explains that while he, like many biologists, was initially resistant to the idea of the mind deeply affecting the body due to its seemingly untestable and ethereal nature, his psychiatrist father always insisted that psychiatric cures work through brain biology. This perspective highlights a revolution in understanding disease processes and daily activities like sleep and eating, and even conditions like cancer and autoimmune diseases, as being influenced by the brain, thus opening new avenues for behavioral control and therapy. Linden introduces the concepts of interoception and exteroception. Exteroceptive senses (sight, touch, hearing) provide information about the external world, while interoceptive senses (e.g., blood sugar levels, gut distension) provide information about the internal state of the self. These inward-pointing senses are crucial for the body-mind conversation. Signals can be conveyed rapidly via electrical neuronal impulses or more slowly through hormones traveling in the bloodstream. The brain also continuously monitors our heart rate, with each pulse having a slight effect on brain arteries, providing a rapid signal. The mind, through the brain, communicates with the body via several mechanisms. The volitional or somatic motor system allows conscious control, such as moving an arm. The autonomic nervous system, which operates below conscious awareness, is divided into the sympathetic (fight-or-flight) and parasympathetic (rest-and-digest) branches, which act in opposition. Hormones, secreted by glands like the pituitary and adrenal, also circulate throughout the body, producing general effects. Finally, the immune system is controlled through specialized immune hormones called cytokines. Linden illustrates the complexity of mind-body interaction with the example of hunger and eating. The decision to eat involves integrating exteroceptive information (e.g., smell of pizza), interoceptive information (stomach not distended, feeling hungry), memory (liking pizza), and visual cues. Further decisions during eating, such as whether to swallow a bite or stop eating, involve fast neural signals from the stomach about distension and content, and slower hormonal signals like glucagon-like peptide 1 (GLP-1) from the small intestine, which suppresses appetite. He highlights that artificial sweeteners, while fooling oral sugar sensors, do not fool those in the gut, leading to conflicting brain signals and potentially explaining their ineffectiveness for weight loss. This understanding has led to the development of GLP-1-based drugs (like semaglutide and tirzepatide), which mimic GLP-1 by being modified to last longer in the bloodstream. These drugs are highly effective in suppressing appetite, leading to significant weight loss (12-17% of body weight). Beyond weight loss, these drugs appear to offer additional health benefits, possibly due to GLP-1 receptors being present throughout the body (heart, kidneys, liver), suggesting an anti-inflammatory effect. However, these drugs also have side effects like nausea, gastrointestinal distress, and brain fog, and require continuous use. They also lead to muscle mass loss alongside fat loss, necessitating exercise and protein intake. Intriguingly, GLP-1 drugs may suppress other reward-seeking behaviors like alcohol abuse, drug addiction, compulsive shopping, and gambling, suggesting an overlap in brain reward circuitry. This area is under active research. Linden also discusses the benefits of intensive exercise, which, counterintuitively, stimulates appetite but still results in a net caloric deficit. This is partly due to the production of lactate during intense exercise, which, after conjugation with phenylalanine, acts in the brain to suppress appetite. He attributes the rising obesity rates in the US not to genetic changes or toxins, but to food corporations engineering foods to exploit our evolutionary history of famine. In times of scarcity, it was advantageous to consume high-calorie, fatty, or sweet foods to store energy. Modern engineered foods override our natural satiety mechanisms, exploiting this ancient circuit in our brains. The discussion then shifts to "voodoo death," a phenomenon documented by Walter Cannon in 1942, where individuals die due to a belief in a curse. Cannon's theory implicated hyperarousal of the sympathetic nervous system. Modern understanding suggests it's a "one-two punch": sympathetic hyperarousal combined with parasympathetic overactivity (the rest-and-digest system going into overdrive). This only occurs if the individual believes in the curse, highlighting the profound impact of belief on physiology. Linden argues that "voodoo death" is not limited to societies with supernatural beliefs but has modern parallels, such as "broken heart syndrome" or stress-induced cardiomyopathy (tako tsubo cardiomyopathy), where severe emotional distress, like the death of a loved one, can lead to cardiac dysfunction and even death. This is understood as a consequence of sympathetic nervous system activation. Conversely, positive beliefs and mental states can also have beneficial effects. Mind-body medicine not only includes practices like meditation and psychotherapy but also informs the development of conventional therapies. For example, understanding brain-to-body signaling has led to GLP-1 drugs and vagus nerve stimulation devices for conditions like depression. The placebo effect, where inactive treatments produce benefits, is another powerful example of mind-body connection. For pain relief, the placebo effect is linked to the release of natural opioids (endorphins and enkephalins) in the brain, as it can be blocked by naloxone. Placebo effects extend beyond pain, influencing surgical recovery, healing rates, and the immune system. The context of treatment and even classical conditioning (like Pavlov's dogs) can contribute to placebo responses. Remarkably, the placebo effect for pain has been strengthening over decades, particularly in the US, possibly due to direct-to-consumer drug advertising fostering stronger belief in drug efficacy. Even "open-label placebos," where patients are explicitly told they are receiving a sugar pill, can still produce a therapeutic effect, which Linden finds counterintuitive but well-documented. Understanding these signaling pathways could lead to new drugs and devices. Non-invasive brain stimulation techniques are currently crude but are evolving towards more precise manipulation of specific neuronal types, which could be exploited for medical benefits. Linden then shares his personal experience with synovial sarcoma, an aggressive cancer, for which he was given 6 to 18 months to live. He adopted a "nerd's way" of coping by immersing himself in the biological details of his disease. He explains that cancer is not just uncontrolled cell division but also co-opts other body systems, like the immune system and nerve growth, to promote its survival and spread. Tumors secrete neurotrophins (e.g., NGF, BDNF) to attract nerves, and nerves, in turn, secrete molecules like CGRP that suppress anti-tumor immune responses, worsening prognosis. Preventing tumor innervation is a new therapeutic target. Social support and psychotherapy are known to improve outcomes for heart disease and cancer. Animal studies have begun to unravel the biological mechanisms, showing that activating specific brain circuits related to social connection can accelerate heart attack recovery. While not a miracle cure, psychosocial support appears to have a beneficial effect on cancer progression by reducing stress hormone signaling, which is known to promote tumor growth. This understanding can also lead to new drug therapies; for example, beta-blockers, which target noradrenaline receptors, can slow cancer progression in some cases because these receptors are present on tumor cells. Recent randomized controlled studies have definitively shown that exercise significantly improves cancer outcomes, reducing mortality in colon cancer patients by a large margin. This provides strong evidence that exercise itself, not just associated healthy habits, is beneficial. Linden attributes his survival beyond his initial prognosis partly to his wife's "deep and unconditional love." He hypothesizes this works through biological pathways: brain activity patterns related to love and anticipation could convey electrical signals to his tumor, influencing immune cells (T-cells, natural killer cells) to more effectively attack the tumor. He emphasizes that these are biological hypotheses, moving beyond purely spiritual explanations. His experience with terminal illness has profoundly changed his perspective. He realized that the mind is not built to provide objective truth but to predict the near future. This "future predicting circuitry" may explain why humans, across cultures and religions, create stories of an afterlife, as it is difficult to imagine a world without one's own consciousness. Despite not being a person of faith, he finds these cross-cultural ideas compelling as a biological "bug." He expresses profound gratitude for the "miracle" of being a sentient, curious being on this planet, appreciating the "big things" in life—his loved ones and the joy of existence itself.