Many of the conditions that we think of as common illnesses, such as heart failure, high blood pressure, type II diabetes, Alzheimer’s disease, Parkinson’s disease, NASH, and obesity are primarily or entirely recognized based on particular constellations of symptoms and signs. For example, Alzheimer’s disease is diagnosed based on presence of progressive dementia in the absence of other known causes of dementia, such as stroke. The diagnosis ultimately requires confirmation at autopsy of the presence of nerve loss, amyloid plaques, and neurofibrillary tangles in the brain.The causes of Alzheimer’s disease remain controversial.
Disease, in the sense we are using the term, is a specific biological process that disrupts normal biological function in ways that produce illness. Different disease processes can produce the same illness. For example, different pathogens can cause pneumonia; different genetic mutations can cause hemophilia. As this distinction suggests, people who appear to have the same illness—that is, the same constellation of symptoms and signs—may have different diseases. Common illness, such as those mentioned above, are especially likely to include groups of patients with different underlying diseases.
The reason that understanding disease is important to drug development is simple: a major factor determining the success of clinical trials is including patients whose disease is attributable to the mechanism the therapeutic is designed to address and excluding patients whose disease is not, even though those in the latter group may appear similar to those in the former group.
Drug developers refer to the problem of mixing different groups of patients in clinical trials as “heterogeneity.” Testing therapeutics on heterogeneous groups of patients is a major, and costly, reason that clinical trials fail. For example, decades of efforts and the expenditure of billions of dollars to develop therapeutics to modify the course of Alzheimer’s disease have been disappointing. A major reason for this failure, in retrospect, was inclusion of heterogeneous subjects in clinical trials. Alzheimer’s, despite its name, is an illness, not a disease.
Society has a major stake in increasing the efficiency of therapeutic development. Testing well-conceived therapeutics in appropriately homogeneous groups of patients is the key.
The two categories of disease in which cause is most well-defined are infectious diseases and diseases attributable to a single abnormal gene. Not surprisingly, these categories of disease have historically had among the highest probabilities of clinical trial success. Their mechanistic targets are clear and causally linked to clinically distinct outcomes, making it is easy to identify whom to treat. Identifying and understanding different infectious agents has enabled the success of antibiotic development and vaccine development to treat various infectious diseases (including the unprecedented campaign to develop vaccines to prevent COVID-19). Understanding single genetic mutations that cause inherited genetic disorders makes it possible to create precisely tailored therapeutic interventions. A major reason the biotechnology industry has tended to prioritize monogenic disorders (including cancers caused by so-called “driver mutations”) is because of the favorable probabilities created when a single offending gene causes a disease.
