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Testimony on the National Institute of Diabetes and Digestive and Kidney Diseases' FY 1998 Budget by Dr. Phillip Gorden
Director, National Institute of Diabetes and Digestive and Kidney Diseases
National Institutes of Health
Accompanied by
Mr. L. Earl Laurence, Deputy Director, NIDDK
Mr. Charles R. Zellers, Financial Management Officer, NIDDK
Dr. Harold Varmus, Director, NIH
Mr. Dennis P. Williams, Deputy Assistance Secretary, Budget, DHHS

U.S. Department of Health and Human Services

Before the House Appropriations Committee, Subcommittee on Labor, Health and Human Services, Education and Related Agencies
March 4, 1997

Mr. Chairman and Members of the Committee, I am pleased to testify on behalf of the research programs, progress and opportunities of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Our institute has responsibility for the national biomedical research effort to combat some of the most important, chronic diseases in this country, including diabetes, endocrine and metabolic diseases; digestive diseases and nutritional disorders; and diseases of the kidney, urologic tract and blood. These diseases inflict tremendous suffering and health care costs on the American people because they are life-long, debilitating, and often relentless.

In meeting this challenging research mission, we have forged collaborations with other NIH components, as well as with nonprofit foundations and commercial enterprises. Our approach is to deploy resources and capitalize on emerging technologies across the spectrum of the diseases we address. We seek to understand the underlying cause and course of disease and to develop effective treatment and preventive strategies. At different points in time, based on scientific opportunities, we pursue all or some of these avenues, ranging from the most basic studies of molecular biology to major clinical trials.

This "continuum"of research is best illustrated by a few examples. To illustrate this process, let me describe the point on this continuum that is closest to medical practice: clinical trials. In diabetes, we are currently conducting two multicenter primary prevention trials in an attempt to arrest or delay disease onset. The first trial focuses on immune modulation to halt or delay the onset of insulin-dependent diabetes in high-risk children and adolescents. The second trial is focusing on the use of drug therapy and lifestyle changes to prevent or delay the onset of noninsulin-dependent diabetes, which usually occurs in later life and disproportionately affects minorities. These two trials would not have been possible without the knowledge base we have acquired on the cellullar mechanisms of insulin action; the demonstration that special pharmacologic approaches can prevent the onset of insulin-dependent diabetes in experimental animals; the development of highly accurate tests for predicting the risk of developing diabetes; the design of insulin-sensitizing drugs; and the discovery of sophisticated methods for monitoring metabolic control. Our studies have also been bolstered by the results of the Diabetes Control and Complications Trial (DCCT), which clearly demonstrated the efficacy of metabolic control in preventing the nerve, eye, and kidney complications of diabetes--a message that we are broadly disseminating through our diabetes outreach program.

Another example from the NIDDK research continuum is our ongoing clinical trial of methods to ameliorate the course of kidney function deterioration in African - Americans with hypertension. This study would not have been possible without basic research to develop improved methods of measuring kidney function; to understand the natural history and progression of kidney disease; and to develop and demonstrate the protective effect of drugs that affect the microcirculation of the kidney.

A third example from our research continuum is our current study of non-surgical approaches to treating benign prostatic hyperplasia or BPH, one of the most prevalent conditions in our aging population. This trial would not have been possible without the development of drugs that affect prostate size and bladder outlet function.

While we are pursuing clinical trials made possible by our science base, we are also supporting other types of research in the middle of the research continuum, where clinical applications appear promising, but are not yet completely feasible. Here we find rapidly emerging cutting-edge research. These are central discoveries--largely derivative of recent technologic advances--with broad potential application to multiple diseases. A prime example of this cutting-edge science is found in the NIH Special Emphasis Area, "The Genetics of Medicine," which includes studies to sequence and clone disease-causing genes; identify the proteins they produce or regulate; and develop the means to replace, repair or circumvent the defects they cause. Derivative of these new genetic technologies, NIDDK-supported researchers continue to seek new therapeutic approaches to cystic fibrosis by building upon the landmark discoveries of the gene and defective transport protein responsible for this disease. On a parallel track, other researchers have recently discovered two major defects that lead to polycystic kidney disease--one of the most common genetic diseases and a major cause of end stage renal disease. Moreover, this year, four major genetic discoveries have elucidated defects in two forms of maturity-onset diabetes of the young; hereditary pancreatitis; and the iron-storage blood disease, hemochromatosis. It is critical to emphasize that the importance of these discoveries goes far beyond the specific single-gene diseases to which they directly apply. Importantly, they will also allow us to understand mechanisms applicable to more complex diseases such as noninsulin-dependent diabetes and cancer.

Another excellent example from our continuum of cutting-edge research relates to the NIH Special Emphasis Area, "The Biology of Brain Diseases." This includes the NIDDK-funded discovery of the obesity gene and its hormone product, leptin, which works in the brain to regulate both energy intake and utilization. Almost immediately following this landmark advance, a host of related fundamental discoveries were made related to receptors for leptin and neurobiologic connections within the brain that orchestrate the effects of the body's energy-regulation system. This spinoff research has had an enormous positive impact on U.S. pharmaceutical and biotechnology industries. The leptin story is one of the best ways to illustrate the tightly dovetailed relationship between the national investment in NIH science and the national benefits flowing from its commercial application. These burgeoning discoveries have obvious relevance to appetite control and obesity, and--as is often the case in science--are likely to lead to clinical applications for other medical problems such as diabetes, nutritional disorders, infertility, and developmental abnormalities.

Also at the center of the NIDDK research continuum you will find studies focused on pinpointing the causes, natural history, and onset of disease. These relate to the NIH Special Emphasis Area, "New Approaches to Pathogenesis." Here an excellent example is research following up on the discovery that the bacterium H. pylori is a causative agent of peptic ulcer disease. As a result of this finding, several combinations of antibiotic therapy were approved by FDA this past year for eradication of this bacterium, thus preventing costly, recurrent attacks of peptic ulcer. Also approved was a simple, easy and inexpensive breath test for diagnosing the bacterium in patients--without endoscopy. In NIDDK, we are now building upon these clinical developments to help us focus on remaining research questions of disease pathogenesis, including the mechanisms by which H. pylori leads to ulcer disease and, possibly, to gastric cancer.

In closing, I would like to turn to the first part of the NIDDK research continuum--the engine of basic science that drives all our success stories. Because its ultimate use is largely unknown, the critical importance of such fundamental science is sometimes difficult to convey, other than by giving the types of examples I have described today.. What are some of these "technologies of the future" in which NIDDK is investing today? One is transgenic technology, which enables us to alter genes in laboratory animals in order to study their function. One aspect of transgenic technology is the development of experimental mouse models in which a particular gene has been deleted or "knocked out." One effective way knock-out mice are used is to confirm hypotheses about disease-causing genes and to help researchers then develop and test therapeutic strategies. For example, NIDDK researchers have developed "knock-out" animal models of inflammatory bowel disease which both elucidate putative causes of the disease and also suggest the possibility of therapeutic approaches to protect the intestine from injury and possibly prevent the cellular initiation of intestinal cancer. A second use of transgenic technology is to observe the effects of genes whose function in health and disease is unknown and has not even been hypothesized. Here, we are exploiting molecules just discovered in patients with lung cancer, but now known to be important in bone development, with possible relevance to bone diseases such as osteoporosis. While these types of laboratory studies are extremely preliminary, they illustrate the vast but as yet unknown future clinical application of impressive basic science technologies to diseases afflicting the American public.

Another "technology of the future" is structural biology, which enables us to visualize the three-dimensional architecture of molecules. With this knowledge, researchers can then rationally design drugs to closely fit and attach to a molecule in order to inhibit or enhance its activity. Already, structural biologists in the NIDDK intramural program have contributed to elucidating the structure of the p53 tumor suppressor gene widely believed to play a major role in protecting against many forms of cancer. They have also solved the structure of integrase, a protein essential to the cellular integration and replication of the AIDS virus.

Our investment in "technologies of the future" also includes support for the development of vectors for the delivery of gene therapy. One promising delivery system on which we are working is the adeno-associated virus. Another potential vehicle for gene therapy is the primitive, undifferentiated stem cell. Stem cells might be used to introduce healthy genes to the body and to replace or repair defective ones in a host of genetic diseases. Stem cells also offer opportunities for replenishing the bone marrow in a variety of cancers, as well as other potential applications.

Another example of "technologies of the future" is our support of basic research to understand signal transduction--that is, the cellular communication pathways and cascades, through which disease processes are mediated. Here, we are intensely studying a class of signaling proteins called "G-proteins." These proteins were first discovered in an intramural NIDDK laboratory and now have application in essentially every aspect of our clinical science program.

Mr. Chairman, today I have described the continuum of NIDDK research efforts. This continuum encompasses promising multicenter clinical trials. It contains impressive cutting-edge research within NIH Special Emphasis Areas. It is also made up of a significant base of untargeted fundamental research involving "technologies of the future." We deploy our resources at every point on this continuum. We always recognize, however, that basic science--coupled with replenishment of a cadre of talented scientists--remains the essential underpinning of all our efforts. I am confident that this strong commitment to basic science will lead to major medical progress, which will improve the health of all Americans as we prepare for the twenty-first century.

Mr. Chairman, the budget request for NIDDK for FY 1998 is $821,164,000.

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