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(AFTERNOON SESSION, 1:30 P.M., TUESDAY, FEBRUARY 20, 1990)

DEPARTMENT OF HEALTH AND HUMAN SERVICES

NATIONAL INSTITUTES OF HEALTH

NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY

DISEASES

STATEMENT OF DR. PHILLIP GORDEN, DIRECTOR

SUMMARY STATEMENT

Senator HARKIN. The Appropriations Subcommittee on Labor, Health and Human Services, and Education, and Related Agencies will come to order.

This afternoon we have our third panel: In addition to Dr. Raub; Dr. Phillip Gorden, Director of the National Institute of Diabetes and Digestive and Kidney Diseases; Dr. Duane Alexander, Director of the National Institute of Child Health and Human Development; Dr. David Rall, Director of the National Institute of Environmental Health Sciences; and Dr. Phillip Schambra, Director of the John E. Fogarty International Center.

Again, we will just go down that list in the order in which I called it.

First, Dr. Gorden, glad to have you with us. I notice that your Institute celebrates its 40th anniversary this year. We look forward to see what progress you are making. Your request for 1991 is $605.35 million is what my figures show, or about a 4.11 percentincrease.

So welcome to the subcommittee and we will try to go through the different things and we will go back to questioning because some of the questions go back and forth and they are interrelated.

Dr. Gorden, please proceed. All of your statements will be made a part of the record in their entirety and if you would briefly summarize I would sure appreciate it.

Dr. GORDEN. Thank you, Mr. Chairman. This is a special year for us as it is our 40th anniversary. We were signed into law by President Harry Truman in August 1950.

In recognition of this milestone I would like to focus on a few examples of the many contributions of NIDDK's basic and applied research to clinical medicine.

One of the crowning research achievements of the past year is the discovery of the gene that causes cystic fibrosis. Discovery of the cystic fibrosis gene, however, would have been impossible without the earlier Nobel Prize winning research rooted in the NIDDK. The identification of the first enzyme known that could copy DNA, the unraveling of the code by which DNA translates itself into protein-building blocks of the body, and the discovery of the mechanism used by proteins to fold themselves into their proper shapes for activities are all three Nobel Prize winning endeavors.

Forty years ago when this Institute was founded, diabetes was an enigma. Today, we know that there are fundamentally two forms of diabetes: type I or insulin dependent diabetes is an immunologic abnormality where the body's immune system attacks the insulinproducing cells.

We know that a particular gene controls susceptibility to that disease; that is, a particular gene confers either protection or susceptibility to the disease. This gene is not sufficient to cause the disease, but is necessary.

The more prevalent form of diabetes, type II diabetes, or noninsulin dependent diabetes, is also a genetic disease. In this disease, in identical twins, there is a 90-percent chance that if one twin has diabetes the other twin will have diabetes within 5 years. That is a very powerful genetic statement.

At the present time we do not know what genes are involved in this disease, but it is a very important pursuit of the Institute.

Today the clinical management of diabetes is vastly improved. Diabetes can be diagnosed and treated earlier. Recombinant insulin is now available for treatment, a major accomplishment of the biotechnology industry.

Patients can conveniently test their blood sugars at home or at work. Research is also underway on implantable insulin pumps for improvement of the administration of insulin.

End-stage renal disease is another area of major achievement. When the NIDDK was founded in 1950, patients routinely died within days of kidney failure. Now, dialysis and transplantation have completely altered the outlook for end-stage renal disease patients. In addition, a new drug called erythropoietin combats the anemia of dialysis patients, enabling them to return to work and lead more fully productive lives.

Remarkable research advances have likewise been seen in liver disease. Forty years ago liver failure was an absolute death sentence. Today, two-thirds of transplant recipients survive 1 to 3 years after transplantation, and the long-term survival rate continues to improve. The NIDDK has contributed to the development of potent immunosuppressive drugs and organ preservation solutions that have been essential to these advances.

At the same time, we recognize that dialysis and organ transplantation are incomplete measures, and we remain firmly committed to research aimed at preventing end-stage kidney and liver diseases.

Important contributions have been made recently in type B and type C hepatitis in terms of specific therapies.

PREPARED STATEMENT These examples of progress underscore the crucial importance of the Institute's 40 year record of achievement in basic and applied research, which has laid the foundation for landmark advances in biotechnology, drug and device development, and clinical procedures.

Mr. Chairman, the 1991 budget request for the National Institute of Diabetes and Digestive and Kidney Diseases is $605,349,000.

Thank you.

[The statement follows:)

STATEMENT OF DR. PHILLIP GORDEN

I am particularly pleased to be able to testify before the Subcommittee in 1990, the year that the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) celebrates its 40th anniversary. In recognition of this milestone, I would like to focus on four research areas in which this Institute has made major contributions during the past 40 years: cystic fibrosis, diabetes, kidney disease, and liver disease. The progress in these areas exemplifies the crucial importance of this Institute's solid basic research, which has laid the foundation for landmark advances in biotechnology, drug and device development, and clinical procedures.

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For 40 years, NIDDK has been in the vanguard of research on cystic fibrosis, a disease that painfully strikes down and kills children and young adults. Thus it is with a profound sense of accomplishment that we can report the recent discovery of the defective gene and protein responsible for the most prevalent form of this dread disease. This is one of the crowning research achievements of the past year, and the culmination of decades of basic research supported through the collective efforts of several NIH institutes, the Howard Hughes Medical Institute, and the CF Foundation.

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Prior to 1950--the year this Institute was created--cystic fibrosis was one of the most hopeless diseases known. At that time, Arthur Kornberg was a brilliant young biochemist working in a laboratory at the NIH that is now part of the NIDDK intramural research program. In 1956, he discovered the first enzyme known that could copy DNA, the cellular material that is the key to modern molecular biology and genetics. At the time, no one thought this finding had any bearing on cystic fibrosis, but in many ways, Kornberg's work was a precursor of today's recombinant DNA technology, which enabled the discovery of the cystic fibrosis gene. Kornberg went on to receive the Nobel prize for his geminal achievement--the first in a series of Nobel laureates who have roots in the NIDDK.

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Another important benchmark in CF research was in 1953, just three years after this Institute was formed. Paul Di Sant'Agnese, an NIDDK scientist, discovered an abnormality in the sweat of cystic fibrosis patients. This advance led to the first diagnostic test for this disease. In the following years, NIDDK researchers were at the hub of the revolution in molecular biology that later proved essential to the discovery of the CF gene. Marshall Nirenberg spearheaded the unravelling of the code through which DNA translates itself into the protein building blocks of the body. Christian Anfinsen uncovered the mechanism used by proteins to fold themselves into their proper shapes. These scientists won Nobel prizes for their ground-breaking work-work that needed to be accomplished before the secret of cystic fibrosis could be revealed.

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Then, in 1983, NIDDK-supported researchers, who were engaged in pioneering studies of cell membranes, discovered the first fundamental molecular defect in cystic fibrosis. They found that the channels transporting salts through cell membranes in Cf patients did not work correctly. These studies helped to explain the debilitating mucus that impedes the proper functioning of the lungs, the digestive system and the pancreas in CF patients.

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In 1987, NIDDK grantees pinpointed the location of the CF gene to a specific chromosome, and research teams around the world began to narrow their search. Finally, in 1989, a team of NIDDK-supported American and Canadian scientists reported how they had "walked" and "jumped" up and down the chromosome to pinpoint the gene in an approach called "reverse" genetics. In conventional genetics scientists find the defective protein first and work from there to find the gene. In "reverse" genetics, they find the gene first. For the CF researchers, this approach was likened to looking for a broken faucet in a house somewhere in the United States, without the benefit of road maps.

Fortunately, with the tools of modern molecular bioiogy, they succeeded.

The discovery of the CF gene regts solidly on years of prior work in cell biology that has developed in a parallel track with molecular genetics. Such

fundamental, untargeted research has relied for decades upon the support of the Congress and the public. Now, armed with the CF gene, researchers can design membrane study systems to find ways to make the defective protein work correctly, and ultimately, to seek ways to correct the genetic defect in CF patients through gene therapy. We used to call cystic fibrosis a "disease in search of an idea." In 1990, it is a disease for which there is renewed hope and intense research momentum.

The achievement record in diabetes research is similarly impressive, in terms of understanding and managing this disease. Forty years ago, when this Institute was founded, diabetes was an enigma. The discovery of insulin in the 1920s helped prolong the lives of diabetics, but we understood very little of the disease process and of the severe complications that plagued patients: heart and nerve damage, amputations, and blindness. Over the past 40 years, our ability to comprehend and manage diabetes has changed dramatically. Today, we know that diabetes, which affects an estimated 11-12 million Americans, isn't just one disease with one cause. We know that in Type I, or insulin-dependent diabetes, the body's immune system mistakenly destroys the special group of cells that produce insulin. There is a major genetic risk factor for this condition--and we know at least one error in DNA that marks this risk. For Type II diabetes, we know that resistance to insulin is the underlying problem. Genetics plays a role in causing this disease, but life-style risk factors such as obesity also are extremely important. We also know that Type II diabetes disproportionately affects the Black, Hispanic, Native American, Alaska Native and Native Hawaiian populations.

Major advances have also been attained in improved diagnosis and clinical management of diabetes. Today, if you have diabetes, the chances are greater that you have been diagnosed early. This is important in receiving proper medical advice and treatment, especially for anticipating and treating diabetic complications. While insulin shots are still part of the daily routine of many patients, recombinant human insulin is now available as a result of biotechnology. This drug has prevented problems of insulin shortage, contamination, and immune reaction related to the animal products that were previously the only source of insulin. Today, patients can also conveniently test their blood at home or work to see if they need more insulin --making it far less likely that they will take too much and rigk a coma. Recently, the development of an implantable insulin pump has progressed to successful testing for an 18-month period. When the appropriate research on this device is concluded, the pump will offer patients a treatment option that frees them from daily shots, although they must continue to monitor their blood glucose levels. These clinical management techniques are important to patients and their families, empowering them to take control of their disease and live more productive and unencumbered lives.

Another critical advance in diabetes has been the ability to test patients for molecules in their blood that form when glucose levels stay too high over time. This is vital information in monitoring the treatment of a diabetic patient--to know when that person is succeeding in controlling glucose levels, and when he or she needs help. The NIDDK is sponsoring a large multicenter clinical trial to answer the single most important clinical question in diabetes today--whether long-term careful control of blood glucose levels as close to normal as possible can prevent, delay, or ameliorate the development of the blood-vessel damage that is a major complication of diabetes.

During the past 40 years of this Institute's achievements, another example of major research progress has been end stage renal disease (ESRD). When the NIDDK was founded in 1950, there was nothing to offer as a treatment: patients often died within days or weeks of acute kidney failure. Now, three major advances have completely altered the outlook for ESRD patients. The first is dialysis, which can successfully maintain even those patients whose kidneys are useless. Initially, this life-saving procedure was cumbersome and time-consuming. Today, however, kidney dialysis can be performed comfortably and relatively quickly in hospitals, dialysis centers, and at home.

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