STATEMENT OF DR. PHILLIP GORDEN

I am very pleased to testify about the programs of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Last year, on the occasion of our 40th anniversary, we reviewed several major, long-term clinical achievements of the NIDDK. These included progress in kidney dialysis, liver and kidney transplantation, and recombinant DNA commercial production of insulin, human growth hormone, bovine growth hormone, and erythropoietin. These advances represent dramatic treatments for diabetes and liver and kidney diseases, as well as major innovations in American industry and food production. As we enter the last decade of this century, our mission continues to be the advancement of science to improve the health of the American people and to prevent disease. Our major programs encompass diabetes and other endocrine and metabolic diseases; digestive and nutritional disorders; and diseases of the kidney, urinary tract and blood. Underpinning targeted research on these serious health problems are crosscutting areas of science such as molecular understanding of the human genome.

One of the most important NIDDK crosscutting areas is genetics, as exemplified by our cystic fibrosis (CF) research program. Last year, I reported a significant achievement in human genetics research: the discovery by NIDDK grantees of the gene and defective protein product that cause CF. Building upon these discoveries, NIDDK grantees have now taken other giant steps forward in CF research. Recently, they successfully established longterm cell culture systems, which can be manipulated to understand and interrelate more fully the structural and functional characteristics of CF. This past year, NIDDK grantees were able to correct CF in experimental cells in the laboratory--a significant milestone in CF research. Using a virus, they inserted a normal copy of the CF gene into pancreatic cells taken from CF patients. Remarkably, the gene-altered cells produced a normal protein product and attained normal chloride ion transport. These findings suggest that CF is an excellent candidate for emerging gene therapy techniques.

As we now move into the fifth decade of NIDDK research, I am pleased to report yet another landmark in molecular genetics. NIDDK grantees have identified the gene and mutations responsible for Alport's syndrome, an inherited disease of the kidney's filtering system. This discovery is

particularly significant because it is the first primary disease gene ever identified for a disease of the kidneys.

For the many inherited diseases within our mission, the NIDDK is in the forefront of research related to gene therapy. Recently, NIDDK grantees developed methods for targeting gene therapy to specific sites in animals--the liver, muscle, and arterial wall. This research is extremely important because many inborn metabolic diseases will require organ-specific gene therapy. In this regard, the Institute is encouraging studies of genetic expression and recombination; gene targeting; stem cells and growth factors; and gene transfer techniques.

The NIDDK is also committed to research aimed at preventing chronic diseases, and at halting or slowing their progression. For example, we are supporting a major, multicenter clinical trial to determine whether strict control of blood glucose levels can prevent or ameliorate the vascular complications of insulin-dependent diabetes. Another multicenter trial is assessing whether a dietary regimen, combined with blood pressure control, can prevent or slow the progression of chronic renal disease to end-stage renal disease. Such efforts offer the hope of reducing the enormous suffering and costs of chronic diseases, which will escalate as our population ages.

This past year has been a particularly impressive one for research on diabetes, which affects over 11 million Americans at an estimated annual cost of $20 billion. The NIDDK program in diabetes is a comprehensive one, aimed at understanding the genetic and other causes of both the juvenile and adult forms of the disease; finding ways to combat the devastating complications; and alleviating the disproportionate impact diabetes has on our minority populations, including Blacks, Hispanics, and Native Americans and Hawaiians.

An exciting discovery in research on insulin-dependent diabetes is that a pancreatic protein previously known to be an early predictor of the disease is identical to an enzyme normally produced in large quantities in the brain. This knowledge should facilitate the development of a simple blood test to identify--years in advance of clinical disease--those children who are destined for autoimmune destruction of insulin-producing cells. Such knowledge will be valuable as more effective drugs are developed that might arrest the disease in its earliest stages. Research on restoring insulin

production to diabetics also moved forward this year when NIDDK grantees successfully used the thymus of rats as a new site for transplanting insulinproducing cells. With this approach, they enhanced both immune tolerance to grafts at other sites and graft survival.

Progress is also being made in understanding non-insulin-dependent

In

diabetes. Glucose transport mechanisms are emerging as a major new target for potential treatment of this disease. Studies in animals are defining more precisely the cascade of molecular events involved in the production and action of insulin, in order to pinpoint how resistance to insulin occurs. related research, scientists have identified the cell receptor that binds drugs used to treat non-insulin-dependent diabetes, thus paving the way for more effective drug development. A key source of knowledge about the

metabolic abnormalities and complications of non-insulin-dependent diabetes are NIDDK studies of the Pima Indians, who have the world's highest prevalence of this disease.

Applicable to both forms of diabetes are studies on the genetic

components of this disease.

Research clues are helping to narrow the search

for the diabetes genes. Gene mapping strategies are bearing their first

fruits of success with the identification of a linkage of a genetic locus in a rare form of non-insulin-dependent diabetes.

The genetic puzzle of diabetes

remains a complex challenge, however. To help meet this challenge, I am pleased to tell you that the Institute will begin a new Diabetes Interdisciplinary Research Program in 1992 in an innovative partnership with the Juvenile Diabetes Foundation, International. This follows a productive partnership previously established with the Cystic Fibrosis Foundation.

For kidney and urologic diseases research, I am pleased to report several exciting scientific events. With NIDDK grant support, kidney researchers have made inroads in understanding polycystic kidney disease (PKD), in which cyst formation can impair and destroy kidney function. Recently, NIDDK grantees discovered that the combined action of two known growth-promoting chemicals can initiate cyst formation. This finding has already resulted in the testing of candidate drugs in mice with PKD, thus opening new therapeutic windows. In seeking to combat end-stage renal disease (ESRD), the NIDDK is supporting studies to understand the strikingly high incidence of the kidney

disease of diabetes mellitus (KDDM) among the ESRD patient population, and among Native Americans and Blacks. The NIDDK is also studying the genetic causes of KDDM in Native Americans, and is designing a therapeutic intervention study. The NIDDK-supported U.S. Renal Data System is helping to shed light on the natural history of ESRD and its precursor diseases. Based on insights already gained, the NIDDK plans to launch a pilot clinical study in 1992 on kidney disease and hypertension in Blacks. Thus, the NIDDK has intensified basic and clinical research on the kidney diseases that lead to ESRD, for which annual dialysis and transplantation costs are $5.4 billion. Building a strong urologic diseases research program is a high priority. The NIDDK is seeking to intensify high-quality research in interstitial cystitis, a debilitating disease that primarily affects women; benign prostatic hyperplasia (BPH), which most men develop as they age; and diabetes-related urologic disorders. New knowledge about inflammatory mediators, growth factors and basic bladder function is helping to construct a solid science base in urology, from which future clinical achievements will flow. To expand research in pediatric kidney and urologic diseases, the NIDDK will soon be funding its first research center in these fields.

Achievements in blood disease research are moving steadily toward

clinical applications.

The NIDDK was a major research contributor to the

development of recombinant erythropoietin, a drug that has proven outstanding in alleviating the anemia of ESRD patients, and was just recently approved by the FDA for treating the anemia of AIDS patients. In preliminary clinical studies, NIDDK scientists recently demonstrated the effectiveness of the drug hydroxyurea in reducing the complications of sickle cell disease, one of the most devastating diseases of Black Americans. Now, researchers are combining this drug with other agents in attempts to extend clinical improvement. Progress has also been made toward the development of effective oral drugs to remove the excess iron that accumulates in Cooley's anemia patients as a result of frequent blood transfusions. In preliminary NIDDK-supported tests in animals, these oral chelating drugs have shown their ability to remove iron, while appearing to have low toxicity. We also support research on bone marrow transplantation as a treatment method and a vehicle for gene therapy.

In digestive diseases, compelling research advances abound. A broadly

supported multicenter clinical trial has confirmed the results of the pioneering discovery by our intramural scientists that the drug interferon alfa is effective in treating hepatitis B and C. For ulcers, NIDDK grantees have developed a simple, noninvasive breath test for determining which patients have an underlying bacterial infection that can be eradicated by antibiotics. Grantees have also identified a possible marker for inflammatory bowel disease. If this marker can distinguish between the two forms of this disease--ulcerative colitis and Crohn's disease--it may help to reveal their respective causes. In other studies, the immunosuppressive drug FK506 continues to show enormous promise in liver transplantation, with fewer side effects than conventional drugs. With NIDDK support, a useful animal model was developed for primary biliary cirrhosis, which primarily affects women and is the most frequent indication for liver transplantation in adults. also beginning to understand the relationship between obesity and the development of gallstones, and are following closely the new surgical procedure for gallbladder removal.

We are

Malabsorption syndromes, such as celiac

disease, are the focus of studies aimed at identifying factors that decrease or prevent nutrient absorption by the gastrointestinal tract. This knowledge may also be useful in addressing the wasting syndrome of AIDS.

Our nutrition program is breaking new ground in understanding nutrient metabolism and energy expenditure. Of particular concern is obesity, a disproportionate health problem in minority populations and a major risk factor for non-insulin-dependent diabetes, heart disease, gallbladder disease, and other serious illnesses. NIDDK grantees are searching for obesity-related genes in experimental animal models, as well as for mechanisms that regulate the flow of metabolic fuels and lead to the storage of fat.

Achievements in endocrinology and metabolism are applicable to many diseases because of the far-reaching effects of hormones and metabolic processes throughout the body. The Institute's research on the endocrinology and metabolism of bone is highly relevant to combating osteoporosis--a critical health problem of elderly women. NIDDK grantees have identified a number of growth factors that may play an influential role in the regulation of bone metabolism and the osteoporosis disease process. The Institute is