Gastroenterology in the next century: Megatrends in science and practice

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I realize that my presentation may have a somewhat ponderous title, implying that I might possess a crystal ball able to foretell the future. I don′t. But because of my over 40 years of experience in gastroenterology and hepatology, I have been invited to present some speculations about how and in which direction the field may move in the coming century.

Looking back half a century to the end of WWII and China′s liberation, it is astounding how primitive gastroenterology had been at that time. Modern science hardly had touched it and most of the diagnostic and therapeutic dogmas were still those of the 19th century. But over the past 50 years, as modern biomedical science and technology were taking off, gastroenterology and hepatology have profoundly changed. We have witnessed a huge increase in insight into the causes and mechanisms of disease and our diagnostic and therapeutic capabilities have enormously expanded and improved. For example, think of the discovery of the viruses causing infectious hepatitis, of transplantation of the liver, pancreas and small bowel, or the introduction of fiberoptic endoscopy. And to top it all, recall the recent revolution in peptic ulcer disease which unceremoniously toppled old dogmas about gastric acid and made it instead a readily curable infectious disease.

I believe with confidence that this dynamic evolution will continue and probably accelerate in the coming century. And there is no question that it will bring much novel and unanticipated information about currently obscure diseases. And it will greatly refine diagnostic procedures and expand therapeutic choices. What seems more difficult to predict, though, are the directions which this evolution may take, and how we are going to make use of these new opportunities and will pay for them.

The Human Genome Project undoubtedly is an international undertaking that will have an enormous and irreversible impact on the future of gastroenterology and hepatology. Once its ultimate goal will have been reached, presumably early in the next century, the entire human genome will have been sequenced and mapped and it will be possible and perhaps become routine to screen an individual′s entire genome from a simple blood sample. Genetic mutations which result in hereditary diseases of the gastrointestinal tract or the liver will readily be identified. Individuals or families at risk for a hereditary disease may be screened for the genetic defect. And eventually, such screening may become available even for prenatal use.

Sequencing of the full human genome will be usefull in many other circumstances. Many genetic diseases are polygenic, i.e. the phenotypic expression of a primary gene defect is modified by one or several additional as yet unidentified genes. This probably accounts for the wide spectrum of clinical expression that is seen in many primary genetic defects. For example, homozygous Wilson disease, copper storage disease, may clinically present as progressive cirrhosis, as a severe disease of the central nervous system, or as acute hemolytic anemia. This phenotypic variability most likely reflects the polygenic nature of the disease, a hypothesis which will be resolved by the successful sequencing of the human genome.

Another benefit of the genome project will be identification of the genetic factors which determine individual susceptibility to environmental assaults, such as viral, bacterial or fungal infections or exposure to toxins or poisons. Clearly, different people respond to such noxious assaults differently. For example, some experts believe that inflammatory bowel disease, such as ulcerative colitis or Crohn′s disease, may be the result of a genetically determined aberration of the immune response to the trillions of microorganisms that live in the intestinal lumen. Of course, no such genetic defect has ever been found but sequencing o f the genome may change this.

Another example of a differentiated response to a toxin is observed in chronic alcoholism. Surprisingly, only about 25% of severe chronic alcoholics develop cirrhosis of the liver. Why is it that the majority is escaping hepatic injury It clearly is not due to dietary factors or to the preferred alcoholic beverage. Rather, I suspect that this striking difference is caused by genetic factors which determine how the liver is reacting to the metabolic products or reactive oxygen radicals which are produced when alcohol is metabolized. Hopefully, sequencing of the genome in the next century will help to provide plausible answers.

It is likely that the function of most of the genes identified by sequencing of the human genome initially will be unknown and will have to be determined stepwise, one by one. This will be an enormous task which may well take several decades of painstaking investigation. But once this has been accomplished, gastroenterologists of the future will look at intestinal and liver diseases from a vastly different perspective, and they will use treatments which are far beyond today′s imagination.

The Human Genome Project also is crucial for the future of gene therapy of inherited diseases. This is because it will allow identification of the nature of the genetic error in a mutated gene e.g. transposition of a base pair, missense mutations, or deletion of several nucleotide sequences. This information is crucial for construction of the new gene to be transposed.

As you are aware, gene therapy in vivo has been used successfully in animal models and in a few highly selected genetic defects in humans. There still are problems which need to be addressed but I am confident that they will be resolved in the not too distant future. One of these problems concerns the vehicle or vectors which are used the transport the replacing gene to the targeted cells or organ. At present, this generally is accomplished by packaging it into adeno- or retroviruses or more recently into adeno-associated viroids. But these RNA viruses often cause immune or toxic reactions which limit their usefulness as vectors. Most recently (Nature Medicine, March 1998), Kren et al have proposed a very exciting and highly imaginative new approach, using a chimeric RNA/DNA oligonucleotide embedded in a short stretch of DNA. This is coated with a polycation containing a ligand that permits targeting of specific cells. And it is the cells′ own DNA mismatch repair mechanism which is used for integration of the new oligonucleotide into the DNA. This and other new approaches to gene therapy, particularly for hereditary diseases that are expressed in the liver, are holding immense promise and undoubtedly will play a commanding role in the new century.

A second problem with current gene therapy is that the somatic cells selected for gene repairs have a limited natural life span and then undergo apoptosis. A repaired gene therefore can be expressed no longer than the life span of its cell, which may range from a few days for intestinal mucosa cells to several hundred days for hepatocytes. To overcome this time limitation, one would need to repair the genetic defect in embryonic germ cells which at present is neither possible nor ethically justifiable. A more appealing approach might be to target gene therapy to an organ′s stem cell compartment. Stem cells, in addition to producing daughter cells, are replicating themselves. Therefore new genetic information transposed into stem cells′ genome would be immortalized and thereby indefinitely transferred to daughter cells. I believe that in the coming century, such technology may become available which would be a breakthrough in gene therapy, particularly for hereditary defects expressed in the liver. At present, of course, this can be achieved only be orthotopic liver transplantation which has been used for permanent cure of Crigler-Najjar disease, OTC deficiency and hereditary analbuminemia, to name the most prominent.

Another, new and very promising use of gene therapy is in the treatment of primary cancer or malignant metastases of the liver. The majority of malignant tumors exhibits mutations in genes expressing so-called cancer repressor proteins, such as p53, p16 and others, which act primarily by controlling the cell′s mitotic cycle.When these genes are mutated or lost, the result is unregulated cell replication and tumor growth. In animal models, gene therapy targeted specifically to malignant cells was able to reconstitute functioning p53, p16 genes, which led to significant tumor shrinkage and prolonged survival. Although these are preliminary results in animals and the technique needs refinement, I believe that it has enormous promise and eventually may well replace surgery, radiation or chemotherapy.

I have discussed the Human Genome Project and gene therapy in some detail because they are likely to revolutionize the practice of gastroenterology and hepatology. But there are countless other areas where modern molecular biology will make a big difference. For example, there are many obscure disease processes for whose exploration we simply did not have the necessary tools. Here, molecular biology and virology will profoundly expand and improve the future gastroenterologist′s choice of diagnostic and therapeutic options. Because time is limited, I will mention only one: chronic viral hepatitis, notably hepatitis B and C, which world-wide are causing immense morbidity and mortality. Despite remarkable advances, we still do not understand how these viruses survive and cause liver injury nor do we have effective, reliable and safe therapies to arrest progression, let alone to achieve a permanent cure. To many of us, who are old enough to remember the fiasco with steroid treatment of chronic viral hepatitis, the current hyperbole about interferon treatment is astonishing, if not lamentable. I hope and a nticipate than in the new century, chronic viral hepatitis at long last will find a definitive therapy and eventually effective prevention.

And finally, the rapid evolution of molecular biology has created a new discipline, molecular diagnostics, which will offer an ever-increasing number of tests of previously unthinkable sophistication and sensitivity. For example, molecular techniques already are used to quantitate viral loads in viral hepatitis. But a most promising application will be in the search for new infectious agents which to date have escaped detection by available staining or imunologic methods. As you are aware, several gastrointestinal diseases, previously of unknown etiology, have recently been found to be caused by newly discovered microorganisms. The se include of course, peptic ulcer, but also Whipple′s disease, bacillary angio matosis and most recently, nanobacteria which cause connective tissue calcification in scleroderma, sclerosing cholangitis and in the CREST syndrome associated with primary biliary cirrhosis (PNAS, July 1998). But there are several other gastrointestinal diseases of unknown etiology whose clinical and pathological features seem consistent with, if not suggestive of, an infective origin. These include Crohn′s disease, ulcerative colitis, granulomatous hepatitis and sarcoidosis, primary biliary cirrhosis and sclerosing cholangitis. Although many experts have postulated an immunologic origin of these diseases, no convincing evidence has yet been reported. Now that highly sensitive molecular RNA and DNA probes have become available to hunt for elusive microorganisms, I am confident that the search for pathogens in these diseases will be renewed. And I would not be surprise d if one or more would be discovered to have an infectious etiology.

Predicting the future of gastroenterology would be incomplete without briefly considering what new diagnostic and therapeutic instruments and machinery may become available in the next century. Here, progress, driven by intense market competition, is so rapid that precise predictions are quite impossible. Nonetheless, some treads seem to become detectable. Radiology is likely to progress by leaps and bounds, particularly spiral computerized tomography and three-dimensional imaging. They increasingly will replace invasive diagnostic procedures, including fiberoptic endocopy; the only exception will be the novel fiberoptic, laser-induced fluorescence spectroscopy, which has great diagnostic potential. On the ot her hand, Magnetic Resonance Imaging, with its very expensive equipment, appears to be taking a back seat. And in gastrointestinal surgery, a large proportion of invasive procedures will be performed by laparoscopy, which often makes hospitalization unnecessary and thereby reduces costs.

And this brings me to a true mega factor which in a major way will shape and restrain the practice of gastroenterology in the next century. This is the economics of health care. All over the world, per capita costs of medical care are rising steeply, far outpacing the rate of inflation. To a considerable extent, this is due to the accelerated appearance on the market of new or advanced but always more expensive machines, procedures and drugs which seem necessary to keep up with contemporary medicine. In the United States, this continuing price increase has driven health care costs to a level, equaling 15% of gross domestic product, and other developed countries are not far below. Although in the developing world, health care costs generally are lower, the cost increase in proportion is similar. It seems evident that if this trend should continue, health care eventually will consume a major part of the GDP. But I am afraid that as long as medical care continues to be unregulated or is remaining a market commodity, it will be very difficult, if not impossible to bring quality of medical care and its costs into some sort of reasonable balance. Consider, for example, who would be qualified and publicly acceptable as decision makers Would it fall to third party payers, that is insurance companies or health maintenance organizations Or to employers who are funding the costs of health care Or to the medical care establishment, that is to physicians and hospitals Or perhaps to the government However this paramount issue will be resolved, it will have an enormous impact on the future practice of gastroenterology and hepatology, both in the developed and in the developing world. Developing countries are rapidly coming on mainstream in health care as they are striving to catch up with modern Western medicine. But we should care that their evolving markets are not being deluged by the aggressive pharmaceutical and medical equipment industry of the developed world.

Ladies and Gentlemen, in concluding, I believe that this brief glimpse into the science and practice of gastroenterology in the next century offers us a mixed perspective, one of an ever widening disparity between rising opportunities on the one hand, and restrained resources on the other. I am afraid that unless this serious dilemma will be resolved early in the next century, the practice of gas troenterology and the quality of health care world wide will suffer. We need to learn how to cut expenses by volutarily reducing our dependence on technical procedures and expensive equipment, and by avoiding use of only marginally effective medications and surgical interventions. And last but not least, in hopelessly ill patients, we should forgo trying to prolong drying by every means at our disposal. These, I am afraid, will be painful adjustments for the medical establishment, but they must be faced in the coming century.