Maureen Hannley, PhD, is currently Chief of the Research Division of the Department of Otolaryngology and Communication Sciences at Medical College of Wisconsin and Research Consultant for the Triological Society. She formerly served as the Chief Research Officer of the American Academy of Otolaryngology-Head and Neck Surgery Foundation and has held positions at the National Institutes of Health, Stanford University Medical School, and Arizona State University.
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January 2009Sir William Osler’s image of the future would have been very different from the one that we accept as ordinary today. Would he have imagined medical practice with tools such as MRI, stereotactic radiosurgery, antibiotics, cochlear implants, or the human genome? Could Osler have anticipated clinical practice guidelines, ICD and CPT codes, and malpractice insurance? Each generation of physicians and surgeons has seen advances in science and technology that have affected practice patterns and improved patient outcomes. In the 1920s, the mold that would become penicillin was discovered. In the 1940s, chemotherapy emerged as a new treatment for cancer, and the foundations for one of the most important scientific disciplines, molecular biology, were laid. In the 1950s, the first successful polio vaccine was developed, Dr. John Shea performed the first stapedectomy, and Watson and Crick defined the structure of DNA (reported in a one-page paper in Nature!). Widely publicized cases in the 1960s demonstrated that organ transplants from nonrelated donors were possible.
We would not be wrong in anticipating that the 21st century will bring changes of similar magnitude to the laboratory and to medicine. An unprecedented alliance between scientific research and clinical research-translating scientific discoveries to clinical applications-promises to launch a new era in clinical medicine. Molecular diagnosis of preclinical disease is the paradigm of the future: intervening before symptoms appear because the preclinical molecular events are known and because more sophisticated tools will provide the ability to detect at-risk patients.1 A great deal of attention has been directed toward overcoming three blocks to translational research: (1) translating basic science research to human research; (2) translating new clinical knowledge into clinical practice; and (3) translating evidence-based clinical practice into policy.2
The visionary Elias Zerhouni, MD, immediate past Director of the National Institutes of Health, introduced a number of new programs that emphasized the importance of clinical and translational research. With his overview of the advances made by NIH-supported scientists and others in the scientific community, he predicted that in the future, the current model of medicine would be transformed into one that is predictive, personalized, preemptive, and participatory.1 As one might expect, advances in genetics will make many of these future developments possible-some have appeared already. Looking into the proverbial crystal ball, here are some ways in which the four Ps might affect otolaryngology-head and neck surgery.
Translating research into practice requires neither that the clinician read about the research and decide how to implement it clinically, nor that its essentials are viewed in a slide presentation. Rather, the clinician participates in identifying, shaping, and conducting research relevant to clinical practice.Predicting Vulnerability to Disease
Medical genetics will provide the key to prediction, diagnosis, and early intervention, including computational modeling to predict response to cancer treatment and outcomes, based on disease phenotyping, and knowledge of genotype-phenotype interactions. Considerable work is already in progress using proteomics to identify particular proteins, peptides, and mRNA in saliva and using those as noninvasive biomarkers for oral and salivary gland cancers. This approach may also have implications within the process of anticancer drug discovery. Information from proteomic analysis of saliva may contribute to the target discovery and validation, assessment of efficacy and toxicity of candidate drugs.3 A reliable salivary biomarker would also be an attractive, effective alternative to serum testing, and the possibility of developing home testing kits would further facilitate it as a diagnostic aid, enabling patients to monitor their own health at home.4
Personalizing Treatment Strategies through Advanced Biotechnology
A glimpse into the potential of future treatment strategies is afforded by those already available and in use, such as image-guided surgery, robotic surgery, stereotactic radiosurgery, fMRI, and tissue engineering. With an exploding biomedical technology industry and the creation of a new Institute of Biomedical Imaging and Bioengineering at the NIH, progress in this area is assured; technology will become more sophisticated and its uses expanded. It is not unreasonable to expect that the technology to enable human hair cell and nerve regeneration, subjects of such determined investigation for the past two decades, will be perfected, to the benefit of millions of patients. Other treatment options might include brain-machine interfaces, a broader range of implantable devices, and specialized neurofeedback applications such as those now used in physical medicine and rehabilitation.
Personalizing Prevention and Treatment
Minute differences in a person’s genetic profile determine his or her personal characteristics: eye color, height, facial features, and vulnerability to disease. In the future we can expect to see a person’s genetic profile guide drug dosing, and alert providers to the possibility of adverse reactions. A systems approach to disease and its prevention, diagnosis, and treatment will be driven by the relatively new disciplines of genomics and proteomics. This trend has already begun with the investigation of molecular receptors such as epidermal growth factor receptors and estrogen receptors which, when overexpressed, serve to promote and accelerate malignancies in some of the most commonly involved sites such as the breast, lung, and colon. Such an approach will also facilitate treatment of head and neck cancer guided by analysis of the patient’s genetic profile. Identifying the expression of these receptors enable more precise targeting of chemotherapies and development of effective new tumor-specific drugs.5 An example of a successful clinical application of this research is the development of the drug tamoxifen for treatment of estrogen receptor-positive breast cancer.
Preempting Disease before Symptoms and Damage Occur
New tools enabling the preemption or early treatment of common diseases encountered by otolaryngologists-head and neck surgeons are in development. Specific vaccines targeting otitis media and rhinosinusitis may one day be used with the same frequency and effectiveness as the pneumococcal vaccines, saving the health care system billions of dollars in direct and indirect costs. Monoclonal antibodies have the potential to neutralize common pathogenic bacteria such as P. aeruginosa, preempting the development of difficult primary and secondary infections, with the possibility of postoperative prophylactic use. In the future, drugs may be delivered by viral vectors or by nanoparticles able to cross the cell wall when properly configured. If the condition is known or suspected to be genetic rather than acquired, genetic engineering could make it possible to prevent and preempt syndromic deafness and craniofacial defects. The more widespread application of stem cell research will play a significant role in these goals. There would be, of course, serious moral, ethical, social, and legal issues associated with application of these approaches in more than theory for some time.
Partnering with Clinicians to Translate Research into Practice
The second translational block-and potentially the most difficult to overcome-depends on the ability to add the community-based practicing clinician to the research team, and to involve the community as well. One of the most effective ways to accomplish this goal is by designing, developing, and supporting national clinical research networks. Well-established clinical research networks are used to address clinically significant questions by the American Academy of Family Physicians (National Research Network) and the American Academy of Pediatrics (Pediatric Research in Office Settings Network). The American Academy of Otolaryngology-Head and Neck Surgery has made several forays into research networks with COG*ENT, BEST ENT, OCTCG, and the newest network now in development, CHEER. Effective studies on otitis media, rhinosinusitis, tonsillectomy, nasal obstruction, and obstructive sleep apnea were completed through these networks, raising the level of evidence to support treatment effectiveness for several common conditions.
Translating research into practice requires neither that the clinician read about the research and decide how to implement it clinically, nor that its essentials are viewed in a slide presentation. Rather, the clinician participates in identifying, shaping, and conducting research relevant to clinical practice. In this way, he or she generates the data to evaluate firsthand how research, applied to daily practice, can affect patients in his or her practice-i.e., the effectiveness of the principle can be tested on a broad range of patients. Clearly, some projects would most appropriately be conducted in a tertiary referral practice, but many others could easily involve both academic and community-based practitioners and facilitate acceptance by both groups. As one practical clinician observed, If we want more evidence-based practice, we need more practice-based evidence.6
Making the Vision a Reality
Implementing the next-generation tools described above has the potential to improve patient care and advance medical practice significantly. These improvements, however, will require changes on many levels. The new complexity inherent in clinical and research practice will demand equally complex education and training for physicians and translational scientists: Physicians will learn more of the basic research sciences, with special concentration on medical genetics, and scientists will be exposed to a greater range of clinical issues and disease pathobiology. Simulation and computational modeling are expected to receive greater emphasis. The new and expanded roles of bioethics and HIPAA regulations necessitated by the overarching role of clinical genomics will add a new level of complexity to clinical research.
As translational research comes of age, its infrastructure needs will change, expand, and become more complex: Biomedical research has begun a transition to multidisciplinary teams that may include physicians of several specialties, bench scientists, bioengineers, ethicists, pharmacologists, geneticists, computer programmers, and others to develop, test, and plan implementation for new tools and techniques. An important step in this direction has been taken by the NIH with its decision to replace the General Clinical Research Centers (GCRCs) with the highly sought-after Clinical and Translational Science Institutes (CTSIs). In the current economic climate, however, it would be surprising if federal research funding is increased by any significant amount to permit accelerated funding of the CTSIs and clinical research. Industry-sponsored research, therefore, may become a more important source of support.
A final product of all these changes may not be completely welcome to everyone: Otolaryngology and other surgical specialties can anticipate that as more nonsurgical treatment options are developed and become widely available, the practice profiles of those specialties will change. Already, for example, the use of stereotactic radiosurgery to treat vestibular schwannomas and other intracranial conditions is reducing the necessity for craniotomies.
Osler was correct: The future is today, and each today will bring a bright future and a new age of medicine closer.
References
- Zerhouni EA. Transforming medicine through discovery. Major trends in biomedical research. Bull Acad Natl Med 2007;191:1685-94.
- Sung, NS, Crowley WF Jr, Genel M, et al. Central challenges facing the national clinical enterprise. JAMA 2003; 289:1278-87.
- Hu S, Yen Y, Ann D, Wong DT. Implications of salivary proteomics in drug discovery and development: a focus on cancer drug discovery. Drug Discov Today 2007;12:911-6.
- Nagler R, Bahar G, Shpitzer T, Feinmesser R. Concomitant analysis of salivary tumor markers-a new diagnostic tool for oral cancer. Clin Cancer Res 2006;12:3979-84.
- Zhang H, Berezov A, Wang Q, et al. ErbB receptors: from oncogenes to targeted cancer therapies. J Clin Invest 2007;117:2051-8.
- Green LW. Ethics and community-based participatory research: Commentary on Minkler. Health Educ Behav 2004;31:698-701.
©2009 The Triological Society