NEW CHALLENGES IN INTERNAL MEDICINE
0025-7125/92 $0.00 + .20
DEVELOPMENT OF INNOVATIVE THERAPIES IN THE LARGE MULTISPECIALTY CLINIC SETTING Richard N. Re, MD
INTRODUCTION
Medical care is, at heart, a service, provided by the practitioner to the patient-a service that is based both on art and science. As such, health care delivery is intrinsically an evolutionary process driven by advances in science, changes in social mores, and growth in patient expectations. Innovation in basic science drives innovation in clinical care and, indirectly, therefore, changes in the social context in which health care is provided. Similarly, societal perceptions regarding the costs, benefits, and even the morality of medical treatments affect clinical care and alter the direction of basic scientific research. Thus, to be successful, the medical enterprise must meet both the needs of the individual and those of society; therefore, innovation, both in the science and the delivery of health care, will be required for the successful evolution of the health care system. Major university medical centers and academic clinics have traditionally been the generators of the innovative ideas that then are evaluated by, and, where appropriate, adopted by practitioners and clinics nationwide. In this way, medical science progresses in a semi-orderly fashion. It can be argued that those health care delivery organizations that deliberately support innovation as an important component of their programs derive multiple benefits from this course of action. First, the From the Division of Research, AIton Ochsner Medical Foundation, New Orleans, Louisiana THE MEDICAL CLINICS OF NORTH AMERICA VOLUME 76· NUMBER 5' SEPTEMBER 1992
1025
1026
RE
existence of innovation, be it a new clinical therapy or a new approach to health care delivery, tends to attract and maintain an intellectually aware and aggressive medical staff, the type of physicians who are likely to keep abreast of the latest trends and appropriately balance uncertainties in the literature. Moreover, it could be argued that patients cared for in innovative medical centers derive, at least at the margin, advantage from the intellectual breadth of the practitioners caring for them. Second, innovation provides support for training programs at the resident and subspecialty level. It is difficult to conceive of training top flight medical specialists in the absence of an environment rich in innovation and scientific activity. Trainees, in turn, support the aims of clinics and hospitals, not only through their patient care activities but also through their constant challenging of dogma and of the views of staff physicians. Thus, innovation and scientific research aid in the recruitment of a high quality house staff which then feeds back to improve and support the intellectual activities of staff physicians. Third, innovation and scientific research provide novel and effective therapies for patients. In areas as diverse as hypertension, cardiology, infectious disease, and oncology, research therapy is often either the only, or arguably the best, therapy available for seriously afflicted patients. And finally, medical research provides the physicians and other members of health care delivery organizations with the satisfaction of adding to the fundamental base of human knowledge regarding disease and thereby aiding future progress. These benefits of innovation and research are more easily perceived as being associated with biomedical research than with innovation in health care delivery. This is not surprising because it is clear that biomedical research has contributed far more directly to the well-being of patients than has research in health care delivery. Nonetheless, it is likely that, over the next decade, innovation in health care delivery processes will increasingly become appreciated as an important component of the innovation that drives the health care enterprise in beneficial directions. PREPARING FOR THE TWENTY-FIRST CENTURY
If innovation is important to medical progress in normal times, how much more important is it when truly revolutionary changes are occurring in both the science and practice of medicine? It will here be argued that the new revolution in molecular medicine and the coming revolution in health care delivery represent true paradigm shifts in science and public policy that will impact the practice of virtually every physician. Moreover, clinics and hospitals alike will be compelled not only to educate themselves regarding these new forces but also to bend them to productive and constructive ends.
DEVELOPME:--JT OF 1:-\l\:OVATIVE THERAI'IES ll\: THE MULTISPEClALTY CUl\:IC
1027
If one broadly reviews the progress of medicine over the millennium just ending, one can observe that the phenomenological or descriptive phase of medical investigation begun by the ancients gave way to a more scientific medicine in the sixteenth and seventeenth centuries. Anatomic studies began to yield to physiologic observations regarding the circulation of the blood and other body functions. Clinical observations of various infectious diseases gave way to the microbial theory of disease and eventually to the development of vaccination and antibiosis. In a sense, the first great phase of modern scientific medicine was the era in which infectious diseases came to be understood and, in large measure, were rendered amenable to medical therapy. The second of the sometimes overlapping phases of modern medicine was the growth of physiologic and pathophysiologic thinking beginning with the discovery of the circulation of the blood and continuing through Claude Bernard's concept of homeostasis, the internal environment of Homer Smith, and a long series of advances including, for example, present day studies of left ventricular assist devices in patients suffering from end-stage heart disease. This physiologic era of medicine has been enormously productive and has provided such advances as renal dialysis, coronary artery bypass grafting, angioscopy, and a whole host of prostheses. At Ochsner, for example, there is a long, continuing tradition of commitment to the development of new pharmacologic protocols for the treatment of a wide variety of disorders as well as to the development of new surgical techniques and interventional devices such as angioscopes and novel vascular prostheses. Virtually all these efforts find their scientific support in the in sights derived from the study of whole body physiology and speak to the productivity of the physiologic paradigm. With a few notable exceptions, however, the therapies derived from the physiologic era often did not cure but rather palliated. And often they were extremely expensive. The third era of modern medical progress is that of the molecular biology/molecular genetics revolutionan era that is just now beginning and that has grown out of the cellular biology of the first half of this century. This new science has important implications for all of medicine. Cellular and molecular medicine, as the third era of scientific medicine might also be called, has more in common with the era of infectious disease than it does with the era of physiology. This third era is cell based, is generally "low tech," and, therefore, potentially will provide therapies less expensive than those developed in the physiologic era. But molecular medicine is different from the medicine of the two preceding periods in a fundamental way. Whereas previous paradigms viewed the human body as consisting of homeostatic organ systems, each in large measure the purview of a specific medical discipline, molecular medicine views the human body as a colony of diverse cells sharing common features and traits that they utilize differently. This is an important distinction, for whereas the work of the renal physiologist applies almost solely to the kidney, the work of a molecular or cellular biologist on renal cells may find applications in
1028
RE
a wide variety of organs and in a wide variety of disease conditions. For example, platelet-derived growth factor is a peptide factor released by platelets. It was initially studied because of its growth-promoting effects on arterial smooth muscle cells and its potential involvement in atherogenesis. I, 4, 6 However, modern molecular biology has also shown us that this peptide plays an important role in the brain, the embryo, the vascular smooth muscle, and other systems. One can also note that the name "platelet-derived growth factor," like the terms "fibroblast growth factor," "epidermal growth factor," and others, suggests a specificity of action that is more apparent than real. As it turns out, for example, "fibroblast growth factor" is much more widely active than its name implies, stimulating the growth of new vessels (angiogenesis) as well as that of cells other than fibroblasts. 7. 17 Because cellular and molecular medicine focuses on the cell rather than the organ or physiologic system, the techniques it makes available for diagnosis (and soon for therapy) are widely applicable (Table 1). Such procedures as southern analysis, northern analysis, and polymerase chain reaction will soon be routinely employed in the diagnosis of diseases ranging from cancer to lipid disorders, to infectious diseases. Monoclonal antibodies will be used in a similarly wide fashion. If the new transfection techniques (which are currently being developed for use in the heart, the vasculature, and the liver) are perfected, it will likely be possible to use these methodologies to correct a variety of local and systemic metabolic derangements in vivo soon after the start of the next centuryY-13 The techniques used to insert genes encoding normal low density lipoprotein receptors in the liver cells of patients suffering from hypercholesterolemia will not be very different from the techniques used to introduce transforming growth factor-beta (or some similar gene) into the endothelial cells in the vicinity of a recently angioplastied coronary artery lesion in an effort to prevent restenosis. A variety of compounds, including perhaps derivatized oligonucleotides, will be used to interrupt the transcription/translation of oncogenes or to substitute for the products of tumor suppressor genes in patients with various forms of cancer, and thus, a new paradigm will be introduced into oncology-that of tumor cell differentiation-to supplement strategies directed solely at killing tumor cells. Thus, the practitioner of the future, regardless of whether he or she is a cardiologist, endocrinologist, hepatologist, oncologist, or other specialist, will require a working knowledge of molecular medicine if he or she is to practice in an intelligent manner. More to the point, however, dollars, time, effort, and intellect spent in the construction of a molecular medicine research activity can find fruitful application in virtually every branch of medicine. This observation has important implications for the clinic wishing to establish or develop a biomedical research program, just as it has important implications for the pharmaceutical industry wishing to develop new effective drugs and for the agricultural community working to develop heartier, more productive crops and domestic animals. It is now possible to establish mutually supporting laboratories of
DEVELOPMEj\jT OF INNOVATIVE THERAPIES IN THE MlJLTISPLCIALTY CLINIC
1029
Table 1. SELECTED MOLECULAR GENETICS/CELLULAR BIOLOGY TECHNIQUES AND EXAMPLES OF THEIR MEDICAL APPLICATIONS 1. Molecular cloning
• The synthesis of biologically active proteins for use in therapy. Examples include human insulin, growth hormone, interleukin-2, erythropoietin, and many others. • The construction of genetically engineered vaccines.
2. Southern analysis
• The detection of oncogene and tumor suppressor gene abnormalities in premalignant and malignant tissue as an aid in diagnosis and the determination of prognosis. • The determination of a genetic predisposition to diseases like cancer, lipid disorders, atherosclerosis, diabetes, and many others. • The diagnosis of a wide variety of infectious diseases caused by DNA containing organisms or viruses. • The determination of immunoglobulin and surface receptor gene rearrangements as an aid to the differential diagnosis of leukemia.
3. Polymerase chain reaction (PCR)
• Detection of specific DNA (or following reverse transcription, RNA) that is present in extremely low abundance. This technique can be used for the early detection of HIV infection and will likely soon be used in screening for a variety of other disorders as well as in the assessment of response in patients treated with chemotherapy for leukemia. Forensic medical application involving the availability of only small amou nts of tissue.
4. Restriction fragment length polymorph isms (RFPL)
Can provide the probability that a genetic abnormality is present in a patient when the gene responsible for the disease is not known.
5. Northern analysis
Can detect normal or abnormal messenger RNA synthesis. Can be employed to demonstrate ectopic hormone production or the presence of RNA viral infections.
6. Gene transfer
• Offers the prospect of treating genetic disorders, for example, by inserting a functioning LDL receptor gene into the liver cells of patients suffering from homozygous hypercholesterolemia. The possibility of inserting growth suppressor genes into the arterial walls of patients undergoing angioplasty (to prevent restenosis) or of inserting insulin genes into the cells of diabetics is also under study.
7. Transgenic technology
• Permits the development of animals that express an engineered gene in one or more tissues. These animals can be used as models of diseases or as a means to study the function of a gene. In addition, transgenic animals can be used to produce large quantities of biologically active proteins for use as pharmaceuticals.
8. Embryonal stem cell technology
Can be used to make animals homozygous at a desired locus through homologous recombination and thereby provide models of genetic disorders.
9. Adoptive immunotherapy
The use of autologous Iymphocytes (from tumor tissue or peripheral blood, with or without genetiC engineering to augment tumoricidal activity) and Iymphokines in the treatment of human cancers.
10. Monoclonal antibodies (including those derived by genetic engineering)
Can be used in a wide variety of diagnostic procedures for infectious diseases, neoplasia, and other disorders. Potential use as tumoricidal agents. Potential use in the treatment of autoimmune disorders. Use as artificial enzymes.
11. Anti-sense oligonucleotides
Can be used to prevent the translation of specific messenger RNA and in some cases to prevent the transcription of specific genes. These compounds will likely be used soon as topical therapy for viral infections such as herpes but may in time find application in the therapy of many forms of neoplasia.
1030
RE
molecular biology that not only complement one another's research but interface as well with clinical research scientists in multiple medical disciplines. Instead of being compelled to develop free-standing research programs in oncology, cardiology, nephrology, neurology, and the like, one is now free to develop more cost-effective programs in cellular and molecular medicine, each having its own research direction and yet capable of providing intellectual support for smaller, dedicated clinical research programs in each discipline. This approach has met with success at our Institution and others. * The introduction of programs in molecular genetics and cellular biology provides a source of expertise and consultation that can support the efforts of clinicians/ scientists in virtually any medical specialty. This, of course, is not to say that a critical mass of molecular biologist/molecular geneticists could not be associated with each of a clinic's departments in a productive way. Clearly, the more dedicated support a program has, the more likely it is to succeed. Nor should it be assumed that a molecular genetics initiative will make obsolete more traditional approaches to biomedical research because the new science will complement and extend these activities. The concept and potential of a free-standing molecular medicine group are discussed here to emphasize that the new science will permit the introduction of powerful, productive basic science in a clinic setting at reasonable cost. This is so because of the universality of the science of molecular genetics and the powerful synergy that occurs when a critical mass of knowledge in this field is resident in a research center. The advantages of establishing a molecular medicine activity in a large group practice are clear. In addition to the traditional benefits of research, namely the support of an intellectually aware clinical staff, the support of educational programs, and the introduction of innovative therapies, these facilities increasingly will be required if only to maintain medical literacy among clinicians. The medical literature is changing extremely rapidly, and those physicians not routinely exposed to professionals in molecular genetics will find it increasingly difficult to follow and critically interpret the literature. Moreover, those clinics that support programs in this new science will not only find productive avenues of research before them but also will find themselves increasingly participating in a de facto network of similarly minded organizations, such that new biological therapies can be shared rapidly among these institutions. One can obtain some insight into how this will occur when one considers such therapies as lymphokine-activated-killer cell! interleukin-2 therapy for cancer. IS Although in its current form this treatment is only partially effective in most patients, it already has led the way to a whole new approach to cancer therapy using lymphokines and lymphokine-treated lymphocytes derived from cancer patients. For better or worse, only those *At Ochsner, the molecular biology initiative is composed of four distinct but cooperating efforts - cellular immunology, molecular genetics, molecular oncology, and transgenic technology.
DEVELOPMENT OF INNOVATIVE THERAPIES IN THE MULTISPECIALTY CLINIC
1031
facilities capable of working in a novel fashion with both lymphokines and lymphocytes in culture are capable of administering this therapy, just as only properly positioned organizations will have early access to tumor-infiltrating lymphocyte therapy or a variety of gene insertion therapies now being developed. Because biologic therapy will likely become the dominant mode of treatment in the next century, the presence, on site, of basic scientists skilled in the area of cellular and molecular biology will be an important component in the provision of optimal care. In sum, the era of molecular and cellular medicine provides the physician in a group practice with the opportunity to develop and employ a wide variety of innovative therapies in the treatment of human disease. These opportunities will grow exponentially with time. At the same time, this new science challenges all health care delivery organizations and individual physicians to become more aware of its implications and to adopt, in a timely fashion, its diagnostic and therapeutic applications. INNOVATION IN HEALTH CARE DELIVERY
Just as the science of medicine is changing rapidly, so too are the means by which health care is delivered in the United States. The paradigm of the free-standing fee-for-service practitioner is largely giving way to the group practice, the network, and the institutionbased physician. At the same time, the fee-for-service system is coming under increasing fire because of rapid escalation of the cost of care in the absence of rapidly escalating benefit. This criticism has heightened as an increasing number of Americans find themselves uninsured or underinsured. While it is not now possible to predict exactly what changes will occur in the health care delivery system, it does seem clear that changes will come and that new delivery systems-whether they be health maintenance organizations, preferred provider organizations, or some form of National Health Service-will be created in an attempt to produce higher quality care at the lowest possible cost. 8 This analysis, of course, presupposes that quality of care can be measured and improved. Therein lies a major research challenge. The science of measuring the quality of care is undergoing rapid evolution. In the past, quality was measured principally through an analysis of process. That is, hospitals were examined with a view to determining whether proper procedures were in place to assure high quality care. The proper maintenance of records, the meeting of tissue committees, the holding of staff meetings, and similar activities were properly deemed to be indicators of the quality of care rendered. But, as pointed out by Donabedian,5 the quality of health care is a multidimensional entity involving such things as structure, process, outcome, and, as is increasingly being recognized, patient satisfaction. Of late, increasing emphasis has been placed on medical outcome as an indicator
1032
RE
of quality. This emphasis derives from the fact that valid indices of the severity of patient illness are becoming available so as to permit the accurate interpretation of outcome data. 9 , 16 While much research remains to be done before appropriate severity of disease measures can be found and validated for predicting the likelihood of disease-related outcomes such as morbidity, mortality, and functional status, clear progress is being made, At the same time, the industrial science of quality control has been gradually introduced into medical practice. The process of "continuous improvement" was originally formulated by Shewhart et aP6 and Deming 3 and subsequently developed by Juran and Ishikawa. 2 , 10, 14 Recently, Berwick introduced the use of this technology into medical practice, and it is increasingly being adopted by medical groups in the United States. 2 In brief, the process of continuous improvement involves measuring outcomes of importance and determining whether those outcomes are in "statistical control" -that is, whether variations in outcomes are random or not. If variations are not random, specific causes are sought within the system, and any such problems detected are nonpejoratively corrected. Thereafter, quality teams are assembled from all levels of the organization to develop proposals for improving outcomes. Proposals are adopted on a trial basis, and statistical monitoring is performed to determine if improvement in outcome occurs. Alterations in process that produce improvements in outcome are adopted, and the improvement cycle begins again. This approach to statistical quality control is intrinsically different from assuming that certain levels of care or production are "within tolerance." Rather, in a cross-discipline way all workers are involved in continuously improving the quality of the final product or service. It may well be that the coupling of outcome analysis and indices of the severity of patient disease on one hand with statistical quality control and continuous improvement methodology on the other will provide a mechanism for both generating and evaluating enormous innovation in the way health care is delivered. 14 With others, our Research Division is actively exploring this possibility. If achievable and widely applicable, this approach would result in higher quality at lower cost and, thereby, points the way to a solution of at least part of the current health care dilemma. In any event, it is becoming increasingly clear that health services research will soon be a major source of innovation in health care and, therefore, is an enterprise in which the modern clinic should participate either individually or as part of a larger network. Ochsner, for example, conducts in-house health care research but also participates in such collaborative projects as the National Clinics Research Consortium (which links five large clinics for the purpose of conducting research), the Medicare Clinics Pilot Project (a Health Care Finance Administration-sponsored project linking three clinics and three professional review organizations), and the Academic Medical Centers Consortium (which links 12 major medical centers).
DEVELOPMENT OF INNOVATIVE THERAPIES IN THE MULTISPECIALTY CLINIC
1033
SUMMARY Innovation is intrinsic to medicine and to medical progress. As American medicine enters the twenty-first century, it is confronted with enormous opportunities to innovate both in the science and practice of medicine. Indeed, medicine is challenged to do so by society. Cellular and molecular medicine, along with new insights derived from health care research, offer the opportunity to improve the health of the American people without unduly taxing the economy. Research and innovation in these areas are within the grasp of many clinics, and it would seem important that, because they are major providers of health care, as many clinics as possible aggressively enter these fields in preparation for delivering health care in the next century. References 1. Barrett TB, Benditt EP: 5is (platelet derived growth factor B chain) gene transcription levels are elevated in human atherosclerotic lesions compared to normal artery. Proc Natl Acad Sci 84:1099-1103, 1987 2. Berwick OM: Measuring health care quality. Pediatr Rev 10(1):11-16, 1988 3. Deming WE: Out of the Crisis. Cambridge, Massachusetts Institute of Technology, Center for Advanced Engineering Studies, 1989, p 489 4. Deuel TF, Huang JS: Platelet-derived growth factor: structure, function, and roles in normal and transformed cells. J Cl in Invest 74:669, 1984 5. Donabedian A: Evaluating the quality of medical care. Milbank Memorial Fund Quarterly 44:166-206, 1966 6. Doolittle RF, et al: Simian sarcoma virus onc gene, v-sis is derived from the gene (or genes) encoding a platelet-derived growth factor. Science 221:275, 1983 7. Folkman J, Klagsbrun M: Angiogenic factors. Science 235:442-447, 1987 8. Fuchs VR, Hahn JS: How does Canada do it?: A comparison of expenditures for physicians' services in the United States and Canada. N Engl J Med 323:884-890, 1990 9. Iezzoni LI: Measuring the severity of illness and case mix. In Goldfield N, Nash DB (eds): Providing Quality Care: The Challenge to Clinicians. Philadelphia, American College of Physicians, 1989, p 70-105 10. Ishikawa K: Guide to Quality Control. Tokyo, Japan, Asian Productivity Organization, 1982 11. Marx J: New genes for ailing hearts? Science 248:1492, 1990 12. Moffat AS: Animal cells transformed in vivo. Science 248:1943, 1990 13. Nabel EG, Nabel GJ: Gene transfer and cardiovascular disease. Trends in Cardiovascular Disease 1:12-17, 1991 14. Re RN, Krousel-Wood MA: How to use continuous quality improvement theory and statistical quality control tools in a multispecialty clinic. Q Rev Bull 16:391-397, 1990 15. Rosenberg SA, Lotze MT, Mule JJ: New approaches to the immunotherapy of cancer using interleukin-2. Ann Intern Med 108:853-864, 1988 16. Shewhart AL, Greenfield S, Hoys RD: Functional status and well-being of patients with chronic conditions. Results from the Medical Outcomes Study. JAMA 262:907913, 1989 17. Yayon A, Klagsbrun M, Esko JD, et al: Cell surface, heparin-like molecules are required for binding of basic fibroblast growth factor to its high affinity receptor. Cell 64:841-848, 1991
Address reprint requests to Richard N. Re, MD Division of Research Alton Ochsner Medical Foundation 1516 Jefferson Highway New Orleans, LA 70121
0025-7125/92 $0.00 + .20
DEVELOPMENT OF INNOVATIVE THERAPIES IN THE LARGE MULTISPECIALTY CLINIC SETTING Richard N. Re, MD
INTRODUCTION
Medical care is, at heart, a service, provided by the practitioner to the patient-a service that is based both on art and science. As such, health care delivery is intrinsically an evolutionary process driven by advances in science, changes in social mores, and growth in patient expectations. Innovation in basic science drives innovation in clinical care and, indirectly, therefore, changes in the social context in which health care is provided. Similarly, societal perceptions regarding the costs, benefits, and even the morality of medical treatments affect clinical care and alter the direction of basic scientific research. Thus, to be successful, the medical enterprise must meet both the needs of the individual and those of society; therefore, innovation, both in the science and the delivery of health care, will be required for the successful evolution of the health care system. Major university medical centers and academic clinics have traditionally been the generators of the innovative ideas that then are evaluated by, and, where appropriate, adopted by practitioners and clinics nationwide. In this way, medical science progresses in a semi-orderly fashion. It can be argued that those health care delivery organizations that deliberately support innovation as an important component of their programs derive multiple benefits from this course of action. First, the From the Division of Research, AIton Ochsner Medical Foundation, New Orleans, Louisiana THE MEDICAL CLINICS OF NORTH AMERICA VOLUME 76· NUMBER 5' SEPTEMBER 1992
1025
1026
RE
existence of innovation, be it a new clinical therapy or a new approach to health care delivery, tends to attract and maintain an intellectually aware and aggressive medical staff, the type of physicians who are likely to keep abreast of the latest trends and appropriately balance uncertainties in the literature. Moreover, it could be argued that patients cared for in innovative medical centers derive, at least at the margin, advantage from the intellectual breadth of the practitioners caring for them. Second, innovation provides support for training programs at the resident and subspecialty level. It is difficult to conceive of training top flight medical specialists in the absence of an environment rich in innovation and scientific activity. Trainees, in turn, support the aims of clinics and hospitals, not only through their patient care activities but also through their constant challenging of dogma and of the views of staff physicians. Thus, innovation and scientific research aid in the recruitment of a high quality house staff which then feeds back to improve and support the intellectual activities of staff physicians. Third, innovation and scientific research provide novel and effective therapies for patients. In areas as diverse as hypertension, cardiology, infectious disease, and oncology, research therapy is often either the only, or arguably the best, therapy available for seriously afflicted patients. And finally, medical research provides the physicians and other members of health care delivery organizations with the satisfaction of adding to the fundamental base of human knowledge regarding disease and thereby aiding future progress. These benefits of innovation and research are more easily perceived as being associated with biomedical research than with innovation in health care delivery. This is not surprising because it is clear that biomedical research has contributed far more directly to the well-being of patients than has research in health care delivery. Nonetheless, it is likely that, over the next decade, innovation in health care delivery processes will increasingly become appreciated as an important component of the innovation that drives the health care enterprise in beneficial directions. PREPARING FOR THE TWENTY-FIRST CENTURY
If innovation is important to medical progress in normal times, how much more important is it when truly revolutionary changes are occurring in both the science and practice of medicine? It will here be argued that the new revolution in molecular medicine and the coming revolution in health care delivery represent true paradigm shifts in science and public policy that will impact the practice of virtually every physician. Moreover, clinics and hospitals alike will be compelled not only to educate themselves regarding these new forces but also to bend them to productive and constructive ends.
DEVELOPME:--JT OF 1:-\l\:OVATIVE THERAI'IES ll\: THE MULTISPEClALTY CUl\:IC
1027
If one broadly reviews the progress of medicine over the millennium just ending, one can observe that the phenomenological or descriptive phase of medical investigation begun by the ancients gave way to a more scientific medicine in the sixteenth and seventeenth centuries. Anatomic studies began to yield to physiologic observations regarding the circulation of the blood and other body functions. Clinical observations of various infectious diseases gave way to the microbial theory of disease and eventually to the development of vaccination and antibiosis. In a sense, the first great phase of modern scientific medicine was the era in which infectious diseases came to be understood and, in large measure, were rendered amenable to medical therapy. The second of the sometimes overlapping phases of modern medicine was the growth of physiologic and pathophysiologic thinking beginning with the discovery of the circulation of the blood and continuing through Claude Bernard's concept of homeostasis, the internal environment of Homer Smith, and a long series of advances including, for example, present day studies of left ventricular assist devices in patients suffering from end-stage heart disease. This physiologic era of medicine has been enormously productive and has provided such advances as renal dialysis, coronary artery bypass grafting, angioscopy, and a whole host of prostheses. At Ochsner, for example, there is a long, continuing tradition of commitment to the development of new pharmacologic protocols for the treatment of a wide variety of disorders as well as to the development of new surgical techniques and interventional devices such as angioscopes and novel vascular prostheses. Virtually all these efforts find their scientific support in the in sights derived from the study of whole body physiology and speak to the productivity of the physiologic paradigm. With a few notable exceptions, however, the therapies derived from the physiologic era often did not cure but rather palliated. And often they were extremely expensive. The third era of modern medical progress is that of the molecular biology/molecular genetics revolutionan era that is just now beginning and that has grown out of the cellular biology of the first half of this century. This new science has important implications for all of medicine. Cellular and molecular medicine, as the third era of scientific medicine might also be called, has more in common with the era of infectious disease than it does with the era of physiology. This third era is cell based, is generally "low tech," and, therefore, potentially will provide therapies less expensive than those developed in the physiologic era. But molecular medicine is different from the medicine of the two preceding periods in a fundamental way. Whereas previous paradigms viewed the human body as consisting of homeostatic organ systems, each in large measure the purview of a specific medical discipline, molecular medicine views the human body as a colony of diverse cells sharing common features and traits that they utilize differently. This is an important distinction, for whereas the work of the renal physiologist applies almost solely to the kidney, the work of a molecular or cellular biologist on renal cells may find applications in
1028
RE
a wide variety of organs and in a wide variety of disease conditions. For example, platelet-derived growth factor is a peptide factor released by platelets. It was initially studied because of its growth-promoting effects on arterial smooth muscle cells and its potential involvement in atherogenesis. I, 4, 6 However, modern molecular biology has also shown us that this peptide plays an important role in the brain, the embryo, the vascular smooth muscle, and other systems. One can also note that the name "platelet-derived growth factor," like the terms "fibroblast growth factor," "epidermal growth factor," and others, suggests a specificity of action that is more apparent than real. As it turns out, for example, "fibroblast growth factor" is much more widely active than its name implies, stimulating the growth of new vessels (angiogenesis) as well as that of cells other than fibroblasts. 7. 17 Because cellular and molecular medicine focuses on the cell rather than the organ or physiologic system, the techniques it makes available for diagnosis (and soon for therapy) are widely applicable (Table 1). Such procedures as southern analysis, northern analysis, and polymerase chain reaction will soon be routinely employed in the diagnosis of diseases ranging from cancer to lipid disorders, to infectious diseases. Monoclonal antibodies will be used in a similarly wide fashion. If the new transfection techniques (which are currently being developed for use in the heart, the vasculature, and the liver) are perfected, it will likely be possible to use these methodologies to correct a variety of local and systemic metabolic derangements in vivo soon after the start of the next centuryY-13 The techniques used to insert genes encoding normal low density lipoprotein receptors in the liver cells of patients suffering from hypercholesterolemia will not be very different from the techniques used to introduce transforming growth factor-beta (or some similar gene) into the endothelial cells in the vicinity of a recently angioplastied coronary artery lesion in an effort to prevent restenosis. A variety of compounds, including perhaps derivatized oligonucleotides, will be used to interrupt the transcription/translation of oncogenes or to substitute for the products of tumor suppressor genes in patients with various forms of cancer, and thus, a new paradigm will be introduced into oncology-that of tumor cell differentiation-to supplement strategies directed solely at killing tumor cells. Thus, the practitioner of the future, regardless of whether he or she is a cardiologist, endocrinologist, hepatologist, oncologist, or other specialist, will require a working knowledge of molecular medicine if he or she is to practice in an intelligent manner. More to the point, however, dollars, time, effort, and intellect spent in the construction of a molecular medicine research activity can find fruitful application in virtually every branch of medicine. This observation has important implications for the clinic wishing to establish or develop a biomedical research program, just as it has important implications for the pharmaceutical industry wishing to develop new effective drugs and for the agricultural community working to develop heartier, more productive crops and domestic animals. It is now possible to establish mutually supporting laboratories of
DEVELOPMEj\jT OF INNOVATIVE THERAPIES IN THE MlJLTISPLCIALTY CLINIC
1029
Table 1. SELECTED MOLECULAR GENETICS/CELLULAR BIOLOGY TECHNIQUES AND EXAMPLES OF THEIR MEDICAL APPLICATIONS 1. Molecular cloning
• The synthesis of biologically active proteins for use in therapy. Examples include human insulin, growth hormone, interleukin-2, erythropoietin, and many others. • The construction of genetically engineered vaccines.
2. Southern analysis
• The detection of oncogene and tumor suppressor gene abnormalities in premalignant and malignant tissue as an aid in diagnosis and the determination of prognosis. • The determination of a genetic predisposition to diseases like cancer, lipid disorders, atherosclerosis, diabetes, and many others. • The diagnosis of a wide variety of infectious diseases caused by DNA containing organisms or viruses. • The determination of immunoglobulin and surface receptor gene rearrangements as an aid to the differential diagnosis of leukemia.
3. Polymerase chain reaction (PCR)
• Detection of specific DNA (or following reverse transcription, RNA) that is present in extremely low abundance. This technique can be used for the early detection of HIV infection and will likely soon be used in screening for a variety of other disorders as well as in the assessment of response in patients treated with chemotherapy for leukemia. Forensic medical application involving the availability of only small amou nts of tissue.
4. Restriction fragment length polymorph isms (RFPL)
Can provide the probability that a genetic abnormality is present in a patient when the gene responsible for the disease is not known.
5. Northern analysis
Can detect normal or abnormal messenger RNA synthesis. Can be employed to demonstrate ectopic hormone production or the presence of RNA viral infections.
6. Gene transfer
• Offers the prospect of treating genetic disorders, for example, by inserting a functioning LDL receptor gene into the liver cells of patients suffering from homozygous hypercholesterolemia. The possibility of inserting growth suppressor genes into the arterial walls of patients undergoing angioplasty (to prevent restenosis) or of inserting insulin genes into the cells of diabetics is also under study.
7. Transgenic technology
• Permits the development of animals that express an engineered gene in one or more tissues. These animals can be used as models of diseases or as a means to study the function of a gene. In addition, transgenic animals can be used to produce large quantities of biologically active proteins for use as pharmaceuticals.
8. Embryonal stem cell technology
Can be used to make animals homozygous at a desired locus through homologous recombination and thereby provide models of genetic disorders.
9. Adoptive immunotherapy
The use of autologous Iymphocytes (from tumor tissue or peripheral blood, with or without genetiC engineering to augment tumoricidal activity) and Iymphokines in the treatment of human cancers.
10. Monoclonal antibodies (including those derived by genetic engineering)
Can be used in a wide variety of diagnostic procedures for infectious diseases, neoplasia, and other disorders. Potential use as tumoricidal agents. Potential use in the treatment of autoimmune disorders. Use as artificial enzymes.
11. Anti-sense oligonucleotides
Can be used to prevent the translation of specific messenger RNA and in some cases to prevent the transcription of specific genes. These compounds will likely be used soon as topical therapy for viral infections such as herpes but may in time find application in the therapy of many forms of neoplasia.
1030
RE
molecular biology that not only complement one another's research but interface as well with clinical research scientists in multiple medical disciplines. Instead of being compelled to develop free-standing research programs in oncology, cardiology, nephrology, neurology, and the like, one is now free to develop more cost-effective programs in cellular and molecular medicine, each having its own research direction and yet capable of providing intellectual support for smaller, dedicated clinical research programs in each discipline. This approach has met with success at our Institution and others. * The introduction of programs in molecular genetics and cellular biology provides a source of expertise and consultation that can support the efforts of clinicians/ scientists in virtually any medical specialty. This, of course, is not to say that a critical mass of molecular biologist/molecular geneticists could not be associated with each of a clinic's departments in a productive way. Clearly, the more dedicated support a program has, the more likely it is to succeed. Nor should it be assumed that a molecular genetics initiative will make obsolete more traditional approaches to biomedical research because the new science will complement and extend these activities. The concept and potential of a free-standing molecular medicine group are discussed here to emphasize that the new science will permit the introduction of powerful, productive basic science in a clinic setting at reasonable cost. This is so because of the universality of the science of molecular genetics and the powerful synergy that occurs when a critical mass of knowledge in this field is resident in a research center. The advantages of establishing a molecular medicine activity in a large group practice are clear. In addition to the traditional benefits of research, namely the support of an intellectually aware clinical staff, the support of educational programs, and the introduction of innovative therapies, these facilities increasingly will be required if only to maintain medical literacy among clinicians. The medical literature is changing extremely rapidly, and those physicians not routinely exposed to professionals in molecular genetics will find it increasingly difficult to follow and critically interpret the literature. Moreover, those clinics that support programs in this new science will not only find productive avenues of research before them but also will find themselves increasingly participating in a de facto network of similarly minded organizations, such that new biological therapies can be shared rapidly among these institutions. One can obtain some insight into how this will occur when one considers such therapies as lymphokine-activated-killer cell! interleukin-2 therapy for cancer. IS Although in its current form this treatment is only partially effective in most patients, it already has led the way to a whole new approach to cancer therapy using lymphokines and lymphokine-treated lymphocytes derived from cancer patients. For better or worse, only those *At Ochsner, the molecular biology initiative is composed of four distinct but cooperating efforts - cellular immunology, molecular genetics, molecular oncology, and transgenic technology.
DEVELOPMENT OF INNOVATIVE THERAPIES IN THE MULTISPECIALTY CLINIC
1031
facilities capable of working in a novel fashion with both lymphokines and lymphocytes in culture are capable of administering this therapy, just as only properly positioned organizations will have early access to tumor-infiltrating lymphocyte therapy or a variety of gene insertion therapies now being developed. Because biologic therapy will likely become the dominant mode of treatment in the next century, the presence, on site, of basic scientists skilled in the area of cellular and molecular biology will be an important component in the provision of optimal care. In sum, the era of molecular and cellular medicine provides the physician in a group practice with the opportunity to develop and employ a wide variety of innovative therapies in the treatment of human disease. These opportunities will grow exponentially with time. At the same time, this new science challenges all health care delivery organizations and individual physicians to become more aware of its implications and to adopt, in a timely fashion, its diagnostic and therapeutic applications. INNOVATION IN HEALTH CARE DELIVERY
Just as the science of medicine is changing rapidly, so too are the means by which health care is delivered in the United States. The paradigm of the free-standing fee-for-service practitioner is largely giving way to the group practice, the network, and the institutionbased physician. At the same time, the fee-for-service system is coming under increasing fire because of rapid escalation of the cost of care in the absence of rapidly escalating benefit. This criticism has heightened as an increasing number of Americans find themselves uninsured or underinsured. While it is not now possible to predict exactly what changes will occur in the health care delivery system, it does seem clear that changes will come and that new delivery systems-whether they be health maintenance organizations, preferred provider organizations, or some form of National Health Service-will be created in an attempt to produce higher quality care at the lowest possible cost. 8 This analysis, of course, presupposes that quality of care can be measured and improved. Therein lies a major research challenge. The science of measuring the quality of care is undergoing rapid evolution. In the past, quality was measured principally through an analysis of process. That is, hospitals were examined with a view to determining whether proper procedures were in place to assure high quality care. The proper maintenance of records, the meeting of tissue committees, the holding of staff meetings, and similar activities were properly deemed to be indicators of the quality of care rendered. But, as pointed out by Donabedian,5 the quality of health care is a multidimensional entity involving such things as structure, process, outcome, and, as is increasingly being recognized, patient satisfaction. Of late, increasing emphasis has been placed on medical outcome as an indicator
1032
RE
of quality. This emphasis derives from the fact that valid indices of the severity of patient illness are becoming available so as to permit the accurate interpretation of outcome data. 9 , 16 While much research remains to be done before appropriate severity of disease measures can be found and validated for predicting the likelihood of disease-related outcomes such as morbidity, mortality, and functional status, clear progress is being made, At the same time, the industrial science of quality control has been gradually introduced into medical practice. The process of "continuous improvement" was originally formulated by Shewhart et aP6 and Deming 3 and subsequently developed by Juran and Ishikawa. 2 , 10, 14 Recently, Berwick introduced the use of this technology into medical practice, and it is increasingly being adopted by medical groups in the United States. 2 In brief, the process of continuous improvement involves measuring outcomes of importance and determining whether those outcomes are in "statistical control" -that is, whether variations in outcomes are random or not. If variations are not random, specific causes are sought within the system, and any such problems detected are nonpejoratively corrected. Thereafter, quality teams are assembled from all levels of the organization to develop proposals for improving outcomes. Proposals are adopted on a trial basis, and statistical monitoring is performed to determine if improvement in outcome occurs. Alterations in process that produce improvements in outcome are adopted, and the improvement cycle begins again. This approach to statistical quality control is intrinsically different from assuming that certain levels of care or production are "within tolerance." Rather, in a cross-discipline way all workers are involved in continuously improving the quality of the final product or service. It may well be that the coupling of outcome analysis and indices of the severity of patient disease on one hand with statistical quality control and continuous improvement methodology on the other will provide a mechanism for both generating and evaluating enormous innovation in the way health care is delivered. 14 With others, our Research Division is actively exploring this possibility. If achievable and widely applicable, this approach would result in higher quality at lower cost and, thereby, points the way to a solution of at least part of the current health care dilemma. In any event, it is becoming increasingly clear that health services research will soon be a major source of innovation in health care and, therefore, is an enterprise in which the modern clinic should participate either individually or as part of a larger network. Ochsner, for example, conducts in-house health care research but also participates in such collaborative projects as the National Clinics Research Consortium (which links five large clinics for the purpose of conducting research), the Medicare Clinics Pilot Project (a Health Care Finance Administration-sponsored project linking three clinics and three professional review organizations), and the Academic Medical Centers Consortium (which links 12 major medical centers).
DEVELOPMENT OF INNOVATIVE THERAPIES IN THE MULTISPECIALTY CLINIC
1033
SUMMARY Innovation is intrinsic to medicine and to medical progress. As American medicine enters the twenty-first century, it is confronted with enormous opportunities to innovate both in the science and practice of medicine. Indeed, medicine is challenged to do so by society. Cellular and molecular medicine, along with new insights derived from health care research, offer the opportunity to improve the health of the American people without unduly taxing the economy. Research and innovation in these areas are within the grasp of many clinics, and it would seem important that, because they are major providers of health care, as many clinics as possible aggressively enter these fields in preparation for delivering health care in the next century. References 1. Barrett TB, Benditt EP: 5is (platelet derived growth factor B chain) gene transcription levels are elevated in human atherosclerotic lesions compared to normal artery. Proc Natl Acad Sci 84:1099-1103, 1987 2. Berwick OM: Measuring health care quality. Pediatr Rev 10(1):11-16, 1988 3. Deming WE: Out of the Crisis. Cambridge, Massachusetts Institute of Technology, Center for Advanced Engineering Studies, 1989, p 489 4. Deuel TF, Huang JS: Platelet-derived growth factor: structure, function, and roles in normal and transformed cells. J Cl in Invest 74:669, 1984 5. Donabedian A: Evaluating the quality of medical care. Milbank Memorial Fund Quarterly 44:166-206, 1966 6. Doolittle RF, et al: Simian sarcoma virus onc gene, v-sis is derived from the gene (or genes) encoding a platelet-derived growth factor. Science 221:275, 1983 7. Folkman J, Klagsbrun M: Angiogenic factors. Science 235:442-447, 1987 8. Fuchs VR, Hahn JS: How does Canada do it?: A comparison of expenditures for physicians' services in the United States and Canada. N Engl J Med 323:884-890, 1990 9. Iezzoni LI: Measuring the severity of illness and case mix. In Goldfield N, Nash DB (eds): Providing Quality Care: The Challenge to Clinicians. Philadelphia, American College of Physicians, 1989, p 70-105 10. Ishikawa K: Guide to Quality Control. Tokyo, Japan, Asian Productivity Organization, 1982 11. Marx J: New genes for ailing hearts? Science 248:1492, 1990 12. Moffat AS: Animal cells transformed in vivo. Science 248:1943, 1990 13. Nabel EG, Nabel GJ: Gene transfer and cardiovascular disease. Trends in Cardiovascular Disease 1:12-17, 1991 14. Re RN, Krousel-Wood MA: How to use continuous quality improvement theory and statistical quality control tools in a multispecialty clinic. Q Rev Bull 16:391-397, 1990 15. Rosenberg SA, Lotze MT, Mule JJ: New approaches to the immunotherapy of cancer using interleukin-2. Ann Intern Med 108:853-864, 1988 16. Shewhart AL, Greenfield S, Hoys RD: Functional status and well-being of patients with chronic conditions. Results from the Medical Outcomes Study. JAMA 262:907913, 1989 17. Yayon A, Klagsbrun M, Esko JD, et al: Cell surface, heparin-like molecules are required for binding of basic fibroblast growth factor to its high affinity receptor. Cell 64:841-848, 1991
Address reprint requests to Richard N. Re, MD Division of Research Alton Ochsner Medical Foundation 1516 Jefferson Highway New Orleans, LA 70121
