In a New Interview, Denis Noble Suggests Looking for the Causes of Complex Diseases in the Functioning of the Whole Organism
In a New Interview, Denis Noble Suggests Looking for the Causes of Complex Diseases in the Functioning of the Whole Organism
On 12 August, Denis Noble, Emeritus Professor of Cardiovascular Physiology at the University of Oxford, spoke with Live Longer World about his concept of functional networks, in which cells, tissues, and organs work together in a coordinated way. A polygenic risk score converts disease-associated DNA variants into a probability. Noble argues that, once this risk has been estimated, the next step is to identify the impaired function in the body and determine how it might be restored.
When a person climbs a flight of stairs, nerve signals activate the muscles, blood flow supplies them with oxygen, and cellular processes keep every part of the system working. DNA contains the sequences that cells use to produce the proteins required for this activity. The act of taking a step, however, results from the coordinated activity of the organism as a whole. Noble puts it this way: “The functional network determines how the organism uses the resources provided by its DNA.”
This view grew out of physiology. In 1960, Noble developed the first mathematical model of heart cells, which linked processes within individual cells to the rhythm of the heart. In the interview, he applies the same reasoning to complex diseases. He proposes first identifying the impaired function, then tracing the processes that support it, and finally testing whether a treatment restores that function.
Polygenic scores illustrate the limits of this kind of prediction. In an article in BMJ Medicine, the authors examined 926 scores covering 310 diseases. At a five-percent false-positive rate, the median detection rate, defined as the proportion of people with the disease whom the score correctly identified, was 11%. A score estimates the statistical distribution of risk, but it does not identify which processes have disrupted a function of the organism.
When a DNA variant is known to have a causal role in a single-gene disease, Noble considers genetic intervention appropriate. For complex age-related diseases, he proposes starting with the function that needs to be restored and then determining how cells, tissues, and organs support it.