The investment in NIH research has certainly paid off. However, we are continuously faced with serious challenges in the fight against disease and disability. I see five major thematic areas that build on NIH’s recent advances and that could reap substantial downstream benefits for the diagnosis, prevention, and treatment of a long list of diseases, both rare and common.
First Thematic Area: Applying the unprecedented opportunities in genomics and other high-throughput technologies to understand fundamental biology, and to uncover the causes of specific diseases
In the past, most basic science projects in biomedicine required investigators to limit the scope of their studies to some single aspect of cell biology or physiology. The revolution now sweeping biomedical science is an emphasis on comprehensive approaches that identify all of the genes, all of the proteins, and all of the pathways involved in a disease process. Technologies contributing to these advances, many of which only recently have become practical to use on a routine basis, include DNA sequencing, microarray technology, nanotechnology, small molecule screening capabilities, new imaging modalities, and computational biology.
Cancer is a prime example of the potential of high-throughput approaches. Although a lot of information has been gleaned in the past from targeted efforts with certain tumors, the first complete cancer genomes are now becoming available (for leukemia and brain tumor). Stunning revelations are emerging about the genetic lesions that are involved in malignancies. Due partly to ARRA funding, The Cancer Genome Atlas is poised to derive comprehensive information about the causes of 20 major tumor types. It is virtually certain that this information will force a complete revision of diagnostic categories in cancer, and will usher in an era when every cancer will be evaluated in this comprehensive way, allowing an individualized matchup of the abnormal pathways in that specific tumor with the specific drug or therapeutic known to target that pathway.
Another example is the exciting new opportunity to understand how interactions between our bodies and the hundreds of trillions of microbes that live on us and in us (the so-called “microbiome”) can influence health and disease. The inability to culture most of the species that make up the human microbiome severely limited earlier investigations. But all of these organisms have DNA and/or RNA–and so it is now possible to categorize the vast array of species that are present in various body sites, in both healthy and ill individuals. The consequences for our understanding and treatment of a long list of diseases are likely to be profound. Currently, Human Microbiome Project investigators are studying microbial involvement in a range of diseases including psoriasis, Crohn’s disease, ulcerative colitis, and obesity.
Second Thematic Area: Translating basic science discoveries into new and better treatments
Often the path from molecular insight to therapeutic benefit has not been easily or quickly discernible for many disorders. That is changing now. The major factors propelling this change include the discovery of the fundamental molecular defect in hundreds of diseases, new resources that allow the screening of hundreds of thousands of compounds for drugs that target the defective molecule or molecular pathway, and the partnering of academia and industry to bring the strengths of each to the drug development pipeline.
The NIH Therapeutics for Rare and Neglected Diseases (TRND) program, established in FY 2009, is an example of a critical step in the direction of a truly integrated partnership for drug development between NIH and the private sector. TRND will combine experienced, high-level experts from pharmaceutical and biotechnology organizations and academic researchers. These scientists will work together to translate basic research findings into candidate drugs for patients with rare and neglected diseases. This program will allow promising compounds to be taken to the preclinical phase—often referred to as the “Valley of Death” because it is the place where good ideas often die—by modeling its infrastructure and staffing on best practices in the pharmaceutical and biotechnology industries while also capitalizing on the many human, intellectual, and technological resources available at NIH that are not easily accessed by industry.
Another major area that is ripe for major translational advances is the application of various types of stem cells to treatment of human disease. FDA recently approved the first human protocol (for spinal cord injury) involving human embryonic stem cells (hESCs), and the potential for increased Federal support for human embryonic stem cell research will bring into this field many investigators who have been reluctant to participate due to uncertainties regarding Federal funding of research in this area. The recent revelation that skin fibroblasts can be transformed into induced pluripotent stem cells (iPSCs) opens up a powerful new strategy for therapeutic replacement of damaged or abnormal tissues, without the risk of transplant rejection. While much work remains to be done to investigate the possible risks of this approach, there is much excitement about the potential. The development of the iPSC approach stands as one of the most breathtaking advances in basic science in the last several years, and NIH will be making every effort to pursue with maximum speed the therapeutic consequences of iPSCs, hESCs, and adult stem cells.
Third Thematic Area: Putting science to work for the benefit of health care reform
NIH can make substantial contributions to health care reform. For example, in comparative effectiveness research (CER), NIH has supported clinical studies for many years that rigorously evaluate the outcomes of different medical treatment options. Examples include the Diabetes Prevention Program, which demonstrated substantially better benefits of exercise and lifestyle changes over medication in preventing the onset of diabetes, and the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study, which compared older, cheaper antipsychotic drugs with newer ones, demonstrating that the older drugs worked just as well and had a better side-effect profile.
Prevention and personalized medicine is another area where NIH can widely contribute to health care reform. Advances in pinpointing individual genetic and environmental risk factors for disease now make it possible to focus prevention strategies more effectively on those who need them most. For example, including newly derived information about individual genetic risks for colon cancer or prostate cancer in determining the timing of colonoscopy or PSA screening could save lives and save money. Behavioral research focusing on how personalized information about disease risk actually alters health behaviors and clinical outcomes will be a critical component of this program.
Pharmacogenomics is another important area where research can inform health care. Already there is compelling evidence of a correlation between genotype and drug response for more than a dozen drugs, and that number is growing. But prospective studies will be needed for many of these applications, such as the one for warfarin (a widely prescribed anticoagulant), currently underway at NIH. The opportunity to choose the right drug at the right dose for the right person holds great promise for better health, both by avoiding treatments that are not going to work, and by reducing the incidence of adverse drug reactions.
One of the most tragic aspects of our health care system is the widespread presence of disparities in health. The health of racial and ethnic minorities, people living in poverty, people living in rural and remote locations, and other disadvantaged groups in the United States is worse than the health of the overall population. National concerns for these health disparities repeatedly have been expressed as a high priority in national health status reviews (including Healthy People 2010), and attention to this issue will be a critical component of any successful reform of the U.S. health care system. Now, new opportunities are emerging to define the causes and potential solutions for many health disparities, and these call for integration of research on the multifactorial nature of health disparities, including biological and nonbiological factors, and an understanding of the causes of disparities in access to and delivery of health care.
Fourth Thematic Area: Encouraging a greater focus on global health
NIH has a long tradition of supporting research on global health, and recent seminal scientific advances position NIH to make even more important contributions. Examples already in hand include the development of a vaccine against Ebola virus (proven effective in primates) and the recent discovery by NIH researchers of the first new potential drug in 50 years to treat the parasitic disease schistosomiasis.
Much of recent global health research justifiably has been focused on AIDS, tuberculosis, and malaria, given the enormous human toll from these common and life-threatening disorders. NIH is ideally positioned to play a major role in ramping up the discovery phase for these infections, by applying new technologies such as RNAi, high-throughput screening, proteomics, and metabolomics, and tapping into the talents of highly motivated young researchers with a deep understanding of pathogen-host interactions. Combining these technological and human resources will inform future vaccine development and potentially open a vast new range of targets in pathogens and hosts for prevention, diagnostics, and therapeutics. It also is critical to go beyond the focus on the “big three” diseases to apply some of these same strategies to neglected diseases of low-income countries (e.g., roundworm, hookworm, leprosy, African sleeping sickness).
Importantly, we also must respond to the growing challenge of chronic noncommunicable diseases and injuries, which are now responsible for more than half of deaths in the developing world. Studying the causes of diseases such as diabetes and cancer in countries with limited resources can shed important light on pathogenesis and suggest interventions that can be implemented in low-resource settings.
Fifth Thematic Area: Reinvigorating and empowering the biomedical research community
The lifeblood of biomedical research in the United States rests on the talent and dedication of its scientists and an emphasis on innovation—both factors are considered in NIH’s peer review system. The two-level peer review process is much admired and copied by other research agencies around the world. However, the increasing breadth, complexity, and interdisciplinary nature of modern research pose challenges to the traditional review process. To enhance peer review, NIH recently undertook an extensive examination of its review process, and in June 2008, announced a series of concrete steps for improvement. Those include recruiting the best reviewers; shortening proposals to reduce the burden on both applicants and reviewers; adapting the review process to make it as thorough, reliable, fair, and transparent as possible; and focusing more on impact than on methodological details. The effects of these new steps will be closely monitored, and additional reforms that encourage innovation will be undertaken as needed.
NIH-wide innovation now is fostered by the NIH Common Fund, which is designed to support crosscutting innovative projects that require participation of at least two or more Institutes or Centers. Established in law by the NIH Reform Act of 2006, the Common Fund provides a unique opportunity to support research that otherwise might not find a natural home at NIH.
Finally, the success of biomedical research rests squarely on the robustness of NIH training programs for the next generation of basic, translational, and clinical scientists. Multiple issues must be explored including adequacy of support, our role in training foreign scientists, and how best to diversify the scientific workforce. We need to provide the most exciting and positive environment for new scientists possible, where their enthusiasm and creativity will be nurtured in a way that optimizes their scientific creativity and independence.