Genomics, transcriptomics, proteomics, and metabolomics are increasingly helping to uncover the molecular mechanisms underlying many diseases.
By Paul Cerrato, MA, senior research analyst and communications specialist and John Halamka, M.D., Diercks President, Mayo Clinic Platform
The term precision medicine attracted the public’s attention around 2011 when the US National Research Council recommended a new approach to human disease. Since then, thought leaders and clinicians have tried to focus more attention on the individual needs of each patient and have slowly shifted away from the one-size-fits-all model of patient care. The National Institutes of Health defines precision medicine as: “an innovative approach that takes into account individual differences in patients’ genes, environments, and lifestyles.” Although that definition takes a holistic approach to patient care, most of the research in the field has focused on the genetic component. However, genomics is only the tip of the proverbial iceberg, and several studies indicate it is often a small contributing cause of disease.
Among the many -omics that make up this multimodal world, in addition to genomics, are transcriptomics, proteomics and metabolomics.
Genomics focuses on the entire DNA makeup of an individual, which includes about 20,000 genes on 46 chromosomes. Sequencing a patient’s genome can provide valuable information about the risk of specific disorders. For example, a mutation in one of the genes responsible for the creation of hemoglobin produces an abnormally shaped hemoglobin molecule, which in turn results in fragile, sickle shaped red blood cells and catastrophic symptoms.
Transcriptomics analyzes the role of mRNA and non-coding RNA. During transcription, each cell’s DNA serves as a template to synthesize mRNA, which is then involved in the synthesis of body proteins. In effect, transcriptomics measures how genes are expressed, which determines how cells function or malfunction, which in turn influences the development many diseases. Understanding these biochemical processes can help identify the pathological processes underlying disease and generate biomarkers to assist in diagnosis and treatment.
Proteomics looks specifically at all the body proteins that determine how tissues and organs function. Understanding which of these biochemicals are “misfiring” provides important clues that can reveal the root causes of many disorders. Like transcriptomics, it can also give researchers and clinicians valuable biomarkers to help diagnose, treat, and monitor a variety of diseases. These biomarkers are also being used to help identify potential drug targets and help stratify patients for clinical trials. For example, human epidermal growth factor receptor 2 (HERS2) is used to help oncologists locate patients likely to respond to trastuzumab, while CA-125 is being used in the diagnosis of ovarian cancer.
Metabolomics. The body generates numerous byproducts during various chemical reactions. These end products of metabolism can have a profound impact on how the body works and serve as signaling molecules, immune system triggers, and toxins. For example, branched chain amino acids have been linked to ischemic stroke and glutamine seems to be inversely associated with the risk of myocardial infarction. During a large scale analysis, other investigators have found a collection of metabolites associated with Type 2 diabetes. They state that the metabolites “were found to be genetically linked to signalling pathways and clinical traits that are known to be central to T2D pathophysiology, including insulin resistance, glucose tolerance, ectopic fat deposition, energy and lipid regulation, and liver function.” If supported by additional prospective studies, this metabolic profile could serve as a predictive tool to identify patients most likely to develop the disease.
As the figure below illustrates, these omics join a long list of other signals that enable us to design treatment protocols that target an individual’s needs. The list mentions the contributions of diet, social interaction, and several other variables that a person comes in contact with from day to day—the exposome. The interaction of all these data sources has a major impact on the risk of disease and has given rise to a specialty called network medicine. According to thought leaders in the field: “Network Medicine is a scientific discipline that focuses on the interaction between biological components, such as proteins, microRNAs, or metabolites, to understand molecular pathways that underlie the pathogenesis of diseases… Network Medicine has expanded to integrate molecular data with phenotypic features as a means by which to clarify mechanisms driving clinical disorders.”
Conventional wisdom states that most diseases have only one cause. AIDS is caused by HIV and tuberculosis is caused by the Mycobacterium bacterium. But that doesn’t explain why so many people who are exposed to HIV or to the TB microbe never develop these infections. Network Medicine maintains that most diseases are caused by numerous interacting, contributing factors. A person with a genetically robust immune system, a healthy diet, and a low-stress lifestyle is less likely to develop TB. That perspective is consistent with studies that have found undernutrition contributes to about 2.2 million cases of TB annually. Similarly, macronutrient and micronutrient deficiencies seem to increase the likelihood of mother to child transmission of HIV infection.
As we have pointed out in earlier publication, since the 19th century, medicine has focused on specific disease states by linking collections of signs and symptoms to single organs. Joseph Loscalzo, MD, Harvard Medical School, and his colleagues point out that “this organ-based focus of disease also has served as the driving principle underlying basic research into disease pathogenesis at the physiological, biochemical, and molecular levels.” Systems biology and Network Medicine take a more wholistic approach, looking at all the diverse genetic, metabolic, and environmental factors that contribute to clinical disease. Equally important, it looks at the preclinical manifestations of pathology.
The current focus of medicine is much like the focus that an auto mechanic takes to repair a car. The diagnostic process isolates a broken part and it is then repaired or replaced. Similarly, when a clinician detects an infection, they isolate a specific pathogen and attack it with antibiotics or antiviral agents. If cancer is diagnosed, the tumor becomes the target to be destroyed. If gastrointestinal bleeding is detected, we try to locate the source and stop the bleeding. Although this strategy has saved countless lives and reduced pain and suffering, it nevertheless treats the disease and not the patient, with all their unique habits, lifestyle mistakes, environmental exposures, psychosocial interactions, genetic predispositions, and biochemical signals. Multimodal medicine is the future.
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