Personalized Medicine: Words That Mean Just What You Choose?

Although one of the aims of Molecular Therapy is to describe and promote novel personalized therapies, some people are beginning to conclude that the concept of personalized medicine (PM) is merely a marketing tool to increase patient referrals and bolster grant funding. However, there are unquestionable and genuine medical and scientific underpinnings of PM that should improve both the outcome and the cost-effectiveness of disease treatment. Part of the increasing distrust arises because the term “personalized medicine” means different things to different people, with a consequent mismatch between expectations and delivery. In reality, PM can improve three overlapping but distinguishable clinical areas: practice, prognosis and treatment. It is to the last of these that gene and cell therapy has most to contribute. The best medical practice has always been personalized, in the sense of carefully tailoring the available alternatives to fit a patient's specific circumstances. The randomized controlled clinical trial has arguably been the single most important concept to be introduced into medical practice for 100 years, but this approach and the associated move toward evidence- and protocol-based medical practice has undoubtedly had the undesired effect of sometimes providing excessively uniform treatments for specific diseases. This tendency to prescribe one-size-fits-all medicine has been exacerbated—in the United States, at least—by a progressive loss of generalist family physicians, who have familiarity with all aspects of a patient, including age, social circumstances, and comorbidities. Such generalists can guide patients through the confusing array of options presented by specialist consultants, who may be unaware of the full implications of the therapies they propose. Personalized medicine that provides a patient with informed guidance from a disinterested “consigliore” should be a high priority for any health system that is optimized for the patient as a whole rather than for his or her specific, immediate disease. For many diseases, prognosis is crucial, providing information to patients about the likely outcome of their disease and also guiding therapy, given that a disorder that will have a more dangerous or devastating future outcome may justify correspondingly more drastic early therapy. There is, of course, nothing new about personalizing prognosis. My own specialty of hematology has for many years used clinical, morphological, and molecular means to better characterize benign and malignant disorders of the blood, increasing knowledge of pathogenesis and prognosis and thereby improving therapy. Recent advances in a multiplicity of “-omics” platforms have produced an explosion of additional measurable host and disease parameters. Unfortunately, there has been the predictable lag between data acquisition and data interpretation, and as yet there have been few major shifts in classification or prognostic implications equivalent to the remarkable contributions of earlier prognostic indicators, such as the use of cell surface markers or cytogenetic analyses to categorize leukemias. This current disappointment will probably vanish as soon as the annotated data sets reach the critical mass necessary to match disease and patient characteristics to a broad spectrum of disease outcomes. Such knowledge will be invaluable for the design of future clinical trials, allowing the benefits of changes to therapeutic practices to be assessed more quickly and less expensively, and in smaller numbers of patients. But it is in therapeutic applications that personalized medicine offers the greatest hope of transforming medical practice. Therapy may be personalized by choosing a drug or drug regimen that best suits the specifics of a patient's disease or predicted response to individual therapeutic agents. There is nothing new in this concept—microbiological testing, for example, has long been a staple in deciding what antibiotic should be used to treat serious infection, and host genotyping can predict the required dose of some antibiotics. The current novelty arises from the range of disorders to which this approach may now be applied. For example, despite a number of false starts, this approach holds great promise for choosing cancer therapies, which will become ever more important as we better understand the pathogenesis of malignant disease and develop additional targeted small molecules. For gene therapy, too, an understanding of the personalized molecular basis of disease has been critical in the burgeoning and high-profile successes of gene therapy in treating single-gene defects such as those associated with severe immuno­deficiency, blindness, and clotting disorders. An understanding of the molecular basis of some cancers has also helped investigators design oncolytic viruses that selectively replicate in and destroy tumors, and elucidation of the immune response to vectors is reducing adverse events and prolonging transgene expression in a variety of disorders, including hemophilia B. Cell and gene therapies are also capable of even greater levels of personalization to become truly individualized therapies. Again, we cannot pretend that there is anything new about the concept of individualized therapy; all surgical procedures are individualized, and some of these date back to Paleolithic man! The innovation is in the range of benefits that these new cellular biologics can provide. The Journal has dealt before with some of the problems inherent in the broader introduction of individualized cellular therapeutics, but recent well-publicized success in treating cancer with genetically modified T cells and restoring cardiac function after myocardial infarction has greatly increased interest in the area and may lead to novel solutions. Once we integrate these therapeutic aspects of personalized therapies with the practice and prognostic components of the approach, we can truly anticipate that PM will become both economically and clinically desirable, finally harmonizing the personal and the business aspects of treating disease.