Translational Medicine
The history of clinical research spans the centuries. One of the first systematic clinical trials was conducted in the1700s by Dr. James Lind, who demonstrated on board the HMS Salisbury that adding citrus fruits to the diet of sailors could prevent and cure scurvy. This was a classic, controlled clinical experiment in which the proof of success was the positive response seen in the sailors who were fortunate to be in the group given oranges and lemons as a dietary supplement, as opposed to those who were given vinegar, cider, garlic paste, or sea water.
Today, purists might critique the study design due to the lack of a double-blind control, but the results were so clear that even skeptics would probably accept it as evidenced-based. Amazingly, it took four decades after Lind's experiment before the British Admiralty ordered the use of citrus juice on board ships. Translation of clinical research into community practice still lags today, although the timelines are obviously more compressed, and we are working to close the gap even further.
The New Paradigm: Translational Research
Over the years, the controlled clinical trial model has been a foundation of research. In the simplest construct, once we have identified a potentially useful intervention, we treat the patient, perhaps with a promising new medicine, usually comparing the active therapy with a control group. We carefully document the clinical course of each group to determine outcome of the treated patients vs. the controls. Well-designed clinical trials following this model have advanced modern medicine and led to breakthroughs in the prevention and management of disease. But, in today's complex world, traditional clinical research is only part of the equation.
Today, we are entering a new era of medical advances based on the spectrum of integrated research-and-development efforts known as translational research. This is the continuum that allows us to move laboratory discoveries into clinical application as quickly, safely, efficiently, and cost-effectively as possible. And, based on feedback from patients and clinicians, researchers are stimulated to continue seeking answers to new questions — from bench to bedside and back.
At a time when healthcare costs are spiraling out of control, and the considerable expense of drug development is a significant factor in the willingness of public agencies and private industry to sponsor projects, our objective is to shrink the gap between concept and completion of a novel therapeutic intervention that will benefit patients.
With translational research, we apply powerful new technologies to the study of new drugs, first in tissue or pre-clinical models, and then in human subjects. The goal is to learn at the earliest possible point in drug development if a promising new treatment is safe, and if it can improve or save lives. We hope to short-circuit the traditional paradigm by using modern technology to get a signal of efficacy using much smaller numbers of patients compared with a standard clinical trial.
Centers like UC San Diego's Clinical and Translational Research Institute (CTRI) provide a framework to facilitate collaboration among basic scientists, clinical investigators, private industry, community-based clinicians, and patients to accelerate the development of new therapies (our website is http://ctri.ucsd.edu). San Diego is fortunate to have a robust pharmaceutical and biotechnology community to participate in these endeavors, in addition to our region's status as one of the world's leading biomedical research centers. These assets, along with a highly engaged healthcare community, with health systems and physicians throughout the county committed to providing patients access to advanced care and promising clinical studies, position San Diego as a leading center for drug and technology discovery and development.
Three emerging technologies in particular are changing the way we approach clinical research and drug development: biomarkers; advanced imaging technologies; and biomedical informatics.
Biomarkers are molecular flags that can be used to monitor biological systems in the context of a clinical trial. Common examples of biomarkers include cholesterol for cardiovascular disease and hemoglobin A1c for diabetes. More sophisticated biomarkers looking at gene expression, proteomics, or metabolomics can provide a detailed look at the effect of an experimental agent on biological processes. For instance, in my own area of specialty, we could assess whether an agent that blocks a particular enzyme in a disease like rheumatoid arthritis might decrease TNF production in a patient. Because TNF blockade is very effective in this disease, this could be a signal that predicts efficacy in a larger clinical study examining joint swelling and tenderness. As we understand more about pathogenesis and an individual's predisposition to disease, biomarkers also have the potential to be used diagnostically at the earliest stages of disease development, or as predictive indicators of a patient's likely response to certain interventions. If we can determine what subsets of patients are most likely to respond to certain therapies, this will also allow us to improve patient selection as we move forward with a clinical trial.
Advanced imaging technologies give us the same opportunity for early diagnosis and measurement of disease progression, enabling us to begin treatment before the patient has suffered irreversible damage. Through the CTRI, under the leadership of Dr. Robert Mattrey, professor of radiology and director of our Imaging Resource, we can monitor the effects of intervention with standard or experimental therapy utilizing a range of imaging capabilities. These include molecular imaging that can assess cell function, enzyme activity, and gene function, as well as MRI and functional MRI, PET, SPECT, and ultrasound to monitor functional systems such as blood flow and metabolism, anatomical structures such as organs and the musculoskeletal system, and abnormalities such as tumors and damaged neurons. These technologies can give us early insight into whether a novel, therapeutic approach alters disease progress or promotes healing.
Biomedical informatics is the information bridge that has become key to broad-based collaboration and to compiling, mining, and rapidly analyzing the massive data sets collected across disciplines and continents. Biomedical informatics tools enable us to recognize patterns in data that were previously impossible to analyze, and tap into large populations to expedite large-scale studies, engaging study subjects and investigators around the globe. For example, the increasing use of electronic medical records (EMR) in hospitals and medical group systems provides a rich repository of clinical information that can be accessed through HIPAA-compliant systems and correlated to biomarkers, imaging, and clinical responses. The data mining and computational capabilities available through the CTRI's Biomedical Informatics Resource led by Dr. Lucila Ohno-Machado, professor of medicine, and resources like the San Diego Supercomputer Center, California Institute for Telecommunications and Information Technology, and the National Biomedical Computation Resource, all based at UC San Diego, allow us to conduct preliminary validation studies as well as large-scale clinical trials with speed and accuracy never before possible.
With these and other technologies, those of us who are involved in research to prevent and cure disease are excited about the future. The dialogue and collaboration between laboratory scientists, clinical researchers, bioinformatics experts, and physicians committed to improving patient care is bolstered by this arsenal of new technologies.
The basic principles of clinical research forged by Dr. Lind when he fed citrus fruits to a few sailors suffering scurvy still hold true. But today, modern technology supports a virtual superhighway of research activities, leading from molecule to man, resulting in discoveries that will redefine 21st-century medicine.