A new model for the pathogenesis and treatment of chronic diseases

Electron micrograph with false color transmission of a mitochondrion inside a cell. Photo Credit: Thomas Deerinck, National Research Center for Microscopy and Imaging, UC San Diego

Much of modern Western medicine relies on the treatment of immediate and acute damage, ranging from physical lesions to infections, fractures and colds to heart attacks and asthma.

But progress in treating chronic diseases, where the cause of the problem is often unknown – and, in fact, may not even be there – has fallen behind. Chronic conditions such as cancer, diabetes and cardiovascular disease challenge any explanation, not to mention the cure. The Centers for Disease Control and Prevention estimates that more than half of adults and one third of children and adolescents in the United States live with at least one chronic illness. According to the National Institutes of Health, chronic diseases cause more than half of all deaths worldwide.

In a new paper, available online in Mitochondrion before publication, Robert K. Naviaux, MD, Ph.D., professor of medicine, pediatrics, and pathology at the University of California San Diego School of Medicine, believes that Chronic diseases are essentially the consequence of blocking natural healing cycles, particularly by metabolic and cellular disturbances.

"The healing process is a dynamic circle that begins with an injury and ends with healing. The molecular characteristics of this process are universal, "said Naviaux, who also directs the Center for Mitochondrial and Metabolic Diseases at UC San Diego. "New evidence shows that most chronic diseases are caused by a biological response to an injury, not by the initial injury or injury agent. The disease occurs because the body is unable to complete the healing process. "

For example, said Naviaux, melanoma – the most deadly form of skin cancer – can be caused by sun exposure decades ago, damaging DNA that has never been repaired. Post-traumatic stress disorder can occur months or years after healing of the original head injury. A concussion experienced before an earlier concussion is completely resolved usually leads to more severe symptoms and prolonged recovery, even if the second impact is less than the first.

"Progressive dysfunction with recurrent lesions after incomplete healing occurs in all organ systems, not just in the brain," said Naviaux. "Chronic diseases occur when cells find themselves in a repeated loop of incomplete recovery and re-injury, unable to heal completely. This biology is at the origin of almost all known chronic diseases, including susceptibility to recurrent infections, autoimmune diseases such as rheumatoid arthritis, diabetic heart and kidney disease, asthma, lung disease chronic obstructive Alzheimer dementia, cancer and autism spectrum disorders.

For more than a decade, Naviaux and his colleagues have been studying and developing a theory based on the cellular hazard response (CDR), a natural and universal cellular response to injury or stress. In the new article, Naviaux describes the metabolic features of the three stages of the DRC that make up the healing cycle.

"The goal of the CDR is to help protect the cell and start the healing process," Naviaux said, essentially hardening the cell membrane, ceasing to interact with neighbors and withdrawing until the danger disappears.

"But sometimes, the CDR remains stuck. At the molecular level, the cell balance is altered, preventing the completion of the healing cycle and permanently changing the way the cell responds to the world. When this happens, cells behave as if they are still injured or in imminent danger, even if the original cause of the injury or threat has passed. "

Last year, Naviaux conducted a small randomized clinical trial involving 10 boys with autism, treating them with a single dose of a century old drug inhibiting adenosine triphosphate (ATP), a small molecule produced by cellular mitochondria and serving as an alert. siren of danger. When the abnormal signaling of ATP was silenced, the boys treated at the test presented significantly improved communication and social behaviors. They talked, made eye contact and stopped making repetitive movements. But the benefits were transient, disappearing and disappearing as the drug came out of their systems. The Naviaux team is preparing for a longer and longer test in 2019.

In his new article, Naviaux describes in detail how, based on growing evidence, he believes that metabolic dysfunction causes chronic diseases. Progress in the healing cycle, he says, is controlled by mitochondria – the organelles in the most known cells to produce most of the energy cells needed for survival – and metabokines, metabolic signaling molecules to regulate receptors. more than 100 to healing.

"These are abnormalities in metabokin signaling that cause abnormal persistence of normal stages of the cell's dangerous response, creating blockages in the healing cycle," said Navaiux, who explains that some people are recovering faster than men. 39; others. apparently treated successfully can relapse. It is a form of metabolic "dependence" in which the cell being recovered becomes conditioned to its altered state.

Naviaux suggests that science is about to write a second medical book, focused on chronic disease prevention and new treatments for chronic diseases that can help some people recover fully, the old approaches do not. bringing only small improvements with persistent symptoms. for life.

"The idea would be to direct the treatments on the underlying processes that are blocking the healing cycle," he said. "New treatments can only be given for a short time to promote healing, unlike the application of a cast to promote the healing of a broken leg. When the cast is removed, the limb is weak, but over time the muscles recover and the bones that have been broken may be stronger. "

"Once the triggers of a chronic lesion have been identified and eliminated and the persistent symptoms have been treated, we must think about the solution of the underlying problem of impaired healing. By diverting attention from the root causes to the metabolic factors and signaling pathways that sustain chronic disease, we can find new ways not only to end chronic disease, but also to prevent it.

Funding for this research came, in part, from the UCSD Christini Fund, the Lennox Foundation, the Malone Family Foundation, the Autism Research Foundation N, the Mitochondrial Disease Research Fund. UC San Diego. Linda Clark, Jeanne Conrad, Jeff Ansell, Josh Spears, David Cannistraro, the Kirby family and Katie Mano and the Daniel and Kelly White family.

Publication: Robert K. Naviaux, et al., "Metabolic Characteristics and Regulation of the Healing Cycle – A New Model for the Pathogenesis and Treatment of Chronic Disease", Mitochondrion, 2018; doi: 10.1016 / j.mito.2018.08.001