- Email: [email protected]
Genomic Medicine. The Route to Shangri-La?
Archives of Medical Research 33 (2002) 425–427
EDITORIAL
Genomic Medicine. The Route to Shangri-La? Luis Benítez-Bribiesca In the last quarter of this century, as a consequence of biomedical research centered mostly around the gene, medicine has experienced a radical change. This genocentric view brought formidable expectations for understanding, diagnosing, and treating disease ranging from refined molecular diagnosis to gene therapy. After the nearly complete sequencing of the human genome, its discoverers are confident that clues to the origin, diagnosis, and treatment of every disease could progressively emerge from this data (1,2). Not only in the scientific journals where the original research articles were published, but it was also proudly announced in press releases around the world that in this code of codes lies the book of life and that through its proper reading and manipulation all our burdens of disease could disappear. Following this line of thought, a frenzy in biomedical research has emerged to identify a new gene, a mutation, or a gene product to provide a causal explanation or at least a link to a disease phenotype. Hundreds of genes have been identified for an equal number of diseases such as cystic fibrosis, Huntington disease, breast and colon cancer, retinoblastoma, Li-Fraumeni syndrome, Alzheimer’s disease, hemochromatosis, or Niemann-Pick disease. Many more, such as obesity, depression, violence, homosexuality, and other numerous conditions have been linked to specific chromosomal regions. It is also assumed that normal and pathologic behavior depends on proper or aberrant expression of certain genes. It now seems that our genome is the perfect crystal ball to gaze into our biological past, present, and future. Our evolutionary past is represented by the highly conserved sequences, our present is coded in our genes, and our future health can be foreseen through mutations and single nucleotide polymorphisms (2,3). The promise of genomicentric medicine has been stretched very far, assuming that healing or changing our abnormal genes will be enough to prevent and cure our somatic and mental diseases, thus leading us to a state of perfect health and even longevity. It would seem that genomics has opened the path to Shangri-La, the earthly paradise imagined by Hilton in his novel Lost Horizons. But with all its triumphs and cer-
Address reprint requests to: Luis Benítez-Bribiesca, M.D., Unidad de Investigaciones Oncológicas, Centro Médico Nacional Siglo XXI, Av. Cuauhtémoc #330, Col. Doctores, 06725 México, D.F., México. FAX: (52) (55) 5578-6174; E-mail: [email protected]
tainly more to come, genomic medicine has been successful only with very rare diseases, which comprise no more than 5% of all our pathologies. Much less success has been attained, however, in finding genes related to the most common diseases such as cancer, infections, atherosclerosis, and mental disorders. The degree to which pathogenesis of rare diseases has been explained through gene discoveries is not nearly as profound as the flood of papers and journals suggest. The discovery of the gene and protein involved in Huntington’s disease provides a good example of the inadequacy of simple genetics to provide a reasonable pathogenic explanation for the phenotype in this heritable disease. The gene deterministic model is certainly not incorrect—it simply is not enough. Many reports are based solely on statistical associations between polymorphisms and traits, but additional data often contradict the original claims. Quite often, abnormal gene discoveries are correlative but not predictive of disease. Individuals harboring the gene variant do not necessarily have the trait or disease, falling only into a statistically higher risk for developing the phenotype. In most cases, identification of the abnormal sequence may do little to explain how the disease manifests itself (4). Most common illnesses have multiple causes, and only a tiny portion of cases can be attributed to specific gene variants. Furthermore, claims of identifying a gene marker for any of these diseases such as atherosclerosis, Alzheimer’s disease, or diabetes occur only in family clusters of relatively isolated groups and cannot be confirmed in the general population. Molecular genetic research has helped to clarify the genetic contribution to a number of diseases. Highly penetrant mutations responsible for familial clustering of diseases are rare and account for less than 5% of major cancers and coronary heart disease. For instance, the highly penetrant mutations of BRCA1 and BRCA2 genes increase many-fold the risk of developing cancer in women by the age of 70 years. But only about one half of heritable breast cancers are due to faulty genes. In contrast, 95% of mammary malignancies are sporadic or nonfamilial and do not possess altered BRCA1 or BRCA2 genes. In familial colon cancer, a number of high penetrance genes have been identified, such as APC and hMSH1 and hMSH2, and a model of carcinogenesis with progressive accumulation of genetic and chromosomal anomalies was delineated. However, the proportion
0188-4409/02 $–see front matter. Copyright © 2002 IMSS. Published by Elsevier Science Inc. PII S0188-4409(02)00 3 9 3 - 4
426
Benítez-Bribiesca/ Archives of Medical Research 33 (2002) 425–427
of these inherited colonic cancers in the population is approximately 1–5% in all. Schizophrenia is a frequent and disabling mental disorder affecting almost 1% of the general population. A preponderance of evidence unambiguously shows that heritable factors contribute to the development of the disease. Monozygotic twins of schizophrenics have a 49% chance of being affected, whereas dizygotic twins have only a 14% chance. But the search for the genetic anomaly of this mental disorder has failed to render a conclusive result. Similar efforts to find specific genes for a number of diseases such as rheumatoid arthritis, multiple sclerosis, diabetes, atherosclerosis, obesity, and others have encountered comparable fates (4,5). On the other side of the coin are environmental factors. Molecular genetics by and large ignores the role played by non-genetic factors despite recent efforts to incorporate genetics into epidemiology. It has been conclusively demonstrated that the environment is the major determinant in most diseases. Studies of cancer incidence in immigrants show that after one generation they acquire the local incidence of the malignancy. A change of diet in Pima Indians favors a high incidence of obesity and diabetes. The percentage of coronary heart disease, stroke, diabetes, and colon cancer preventable only by life-style modifications ranges from 70 to 90%. This demonstrates that genome and environment engage in a continuous dialog through which the expression of normal genes can be modulated for good or evil by environmental demands. Based on these observations, it is highly likely that most common human diseases are not attributable to single gene variants (6). They should be viewed as multigenetic, multifactorial, or complex disorders. The naïve view of genetic determinism (that complex traits are caused by a single gene) has progressively been faced in the last decade with the stark reality that nearly all human diseases are complex dependent entities to which our genes make a necessary but incomplete contribution. We now realize that human disease phenotypes are the result not only of faulty genes but also mainly of perturbed self-organizing and lawful networks that display system dynamics (7–9). To the contrary, genomic medicine is based on the reductionistic view that the gene is the ultimate actor of all normal and pathologic human processes and that by mastering the gene, good health and longevity can be achieved. In view of the great promises posed by the prevailing paradigm of genomic medicine, a new industry has emerged and is aimed at developing molecular diagnostic tools and better medicines. Hundreds of biotechnological companies have been established, proposing a cornucopia of new drugs, enough to fulfill virtually every imaginable unmet medical need. Biotechnology industries have attracted many investors, amounting to billions of dollars. Despite sound success in agriculture, bacteriology, and animal genetics, medical applications have been slow to develop and not so successful. There is a litany of drugs against cancer, AIDS, metabolic diseases, and so on that work in the laboratory, whether in
cell cultures or animal models but that are useless in humans because of unintended effects or unanticipated metabolism. Through pharmacogenetics, drug companies have promised to be able in the near future to tailor the right drug for the right patient, a fascinating possibility but quite impractical and costly. Biotechnological industries are not philanthropic enterprises; they are focused on obtaining revenues. For that reason, they are eager to expand sales through marketing strategies highlighting and exaggerating the benefits of their products. Genomic and proteomic tools for diagnosis and risk assessment for many illnesses are now on the market and physicians and patients are being convinced that without them there is no medicine at the frontline. However, even assuming all the benefits of these techniques and the possibility of tailoring drugs for individual patients, their cost would be prohibitive for persons with low income and most importantly, for poor countries. Most common diseases in impoverished societies are infectious, parasitic, and nutritional, and it is well known that they can be effectively controlled by simple cost-effective measures such as running water, sewage, and improved nutrition. Yet millions of dollars are being spent on molecular research for amebiasis, cysticercosis, salmonella, and cholera, but so far these investigations have not produced better means for prevention or control of these diseases. A similar situation has occurred with carcinoma of the cervix, the most frequent cancer in developing nations. Despite the great discovery of human papilloma virus as the causative agent and the formidable effort to uncover all its molecular mechanisms, the old vaginal cytology method continues to be the best method for early detection. What is quite troubling is that biomedical research has not been immune to the commercial trends imposed by industry. Many investigators have been hired by biotechnological industries, and some have established their own companies. Universities and research institutes seek joint ventures with private biotechnological industries to profit from patents for technology or new drugs. Granting that this is a clever strategy to obtain generous funds for the everincreasing cost of biomedical research, there is a hidden danger in that these commercial associations can divert the fundamental quest of a basic scientist, i.e., the search for new knowledge, to the ambitious goal of economic profits. There should be no doubt, however, that the wealth of information that genomic biomedical research has provided for understanding the mechanisms of disease has been impressive and has opened new doors for accurate diagnosis and in some cases for effective treatment. It is the monopoly of the “genocentric” idea in medicine that threatens to cancel other means for understanding the most common diseases, which are by all accounts very complex entities (9– 11). The term “genomic medicine” is misleading because it highlights only the role played by genes in the pathogenesis of disease, casting aside epigenetic, environmental, and social factors. Medicine throughout history was never qualified by prevalent discoveries: at the time of Vessalius one
Genomic Medicine
never spoke of “anatomic medicine”, when Schleiden and Schwann proposed their theory, no “cellular medicine” emerged; Pasteur and Koch did not speak of “bacteriological medicine”, Krebs and Cori did not refer to “biochemical medicine”, after the Bunett and Medawar immunological discoveries medicine did not evolve into “immunological medicine”. Even taking into account today’s modern trend, it would be improper to speak of “complexity medicine”. Medicine needs no adjectives but certainly needs the scientific armamentarium offered by all sciences, including biology, biochemistry, physics, informatics, mathematics, epidemiology and of course, genomics.
References 1. R Chakravarti A. To a future of genetic medicine. Nature 2001; 409:822–823.
427
2. Jiménez-Sánchez G, Childs B, Valle D. Human disease genes. Nature 2001;409:853–855. 3. Aach J, Bulyk ML, Church GM, Comander J, Derti A, Shendure J. Computational comparison of two draft sequences of the human genome. Nature 2001;409:856–859. 4. Zweiger G. Transducing the genome. Information, anarchy, and revolution in the biomedical sciences. New York: McGraw-Hill;2001. 5. Eeles RA, Ponder BAJ, Easton DF, Horwich A. Genetic predisposition to cancer. 1st ed. London: Chapman & Hall Medical;1996. 6. Willet WC. Balancing life-style and genomics research for disease prevention. Science 2002;296:695–698. 7. Rees J. Complex disease and the new clinical sciences. Science 2002;296:698–701. 8. Strohman R. Maneuvering in the complex path from genotype to phenotype. Science 2002;296:701–703. 9. Benítez-Bribiesca L. Complexity: the new frontier in biomedical research. Arch Med Res 2000;31:1–2. 10. Chong L, Ray LB. Whole-istic biology. Science 2002;296:1661. 11. Kiberstis P, Roberts L. It’s not just the genes. Science 2002;296:685.
EDITORIAL
Genomic Medicine. The Route to Shangri-La? Luis Benítez-Bribiesca In the last quarter of this century, as a consequence of biomedical research centered mostly around the gene, medicine has experienced a radical change. This genocentric view brought formidable expectations for understanding, diagnosing, and treating disease ranging from refined molecular diagnosis to gene therapy. After the nearly complete sequencing of the human genome, its discoverers are confident that clues to the origin, diagnosis, and treatment of every disease could progressively emerge from this data (1,2). Not only in the scientific journals where the original research articles were published, but it was also proudly announced in press releases around the world that in this code of codes lies the book of life and that through its proper reading and manipulation all our burdens of disease could disappear. Following this line of thought, a frenzy in biomedical research has emerged to identify a new gene, a mutation, or a gene product to provide a causal explanation or at least a link to a disease phenotype. Hundreds of genes have been identified for an equal number of diseases such as cystic fibrosis, Huntington disease, breast and colon cancer, retinoblastoma, Li-Fraumeni syndrome, Alzheimer’s disease, hemochromatosis, or Niemann-Pick disease. Many more, such as obesity, depression, violence, homosexuality, and other numerous conditions have been linked to specific chromosomal regions. It is also assumed that normal and pathologic behavior depends on proper or aberrant expression of certain genes. It now seems that our genome is the perfect crystal ball to gaze into our biological past, present, and future. Our evolutionary past is represented by the highly conserved sequences, our present is coded in our genes, and our future health can be foreseen through mutations and single nucleotide polymorphisms (2,3). The promise of genomicentric medicine has been stretched very far, assuming that healing or changing our abnormal genes will be enough to prevent and cure our somatic and mental diseases, thus leading us to a state of perfect health and even longevity. It would seem that genomics has opened the path to Shangri-La, the earthly paradise imagined by Hilton in his novel Lost Horizons. But with all its triumphs and cer-
Address reprint requests to: Luis Benítez-Bribiesca, M.D., Unidad de Investigaciones Oncológicas, Centro Médico Nacional Siglo XXI, Av. Cuauhtémoc #330, Col. Doctores, 06725 México, D.F., México. FAX: (52) (55) 5578-6174; E-mail: [email protected]
tainly more to come, genomic medicine has been successful only with very rare diseases, which comprise no more than 5% of all our pathologies. Much less success has been attained, however, in finding genes related to the most common diseases such as cancer, infections, atherosclerosis, and mental disorders. The degree to which pathogenesis of rare diseases has been explained through gene discoveries is not nearly as profound as the flood of papers and journals suggest. The discovery of the gene and protein involved in Huntington’s disease provides a good example of the inadequacy of simple genetics to provide a reasonable pathogenic explanation for the phenotype in this heritable disease. The gene deterministic model is certainly not incorrect—it simply is not enough. Many reports are based solely on statistical associations between polymorphisms and traits, but additional data often contradict the original claims. Quite often, abnormal gene discoveries are correlative but not predictive of disease. Individuals harboring the gene variant do not necessarily have the trait or disease, falling only into a statistically higher risk for developing the phenotype. In most cases, identification of the abnormal sequence may do little to explain how the disease manifests itself (4). Most common illnesses have multiple causes, and only a tiny portion of cases can be attributed to specific gene variants. Furthermore, claims of identifying a gene marker for any of these diseases such as atherosclerosis, Alzheimer’s disease, or diabetes occur only in family clusters of relatively isolated groups and cannot be confirmed in the general population. Molecular genetic research has helped to clarify the genetic contribution to a number of diseases. Highly penetrant mutations responsible for familial clustering of diseases are rare and account for less than 5% of major cancers and coronary heart disease. For instance, the highly penetrant mutations of BRCA1 and BRCA2 genes increase many-fold the risk of developing cancer in women by the age of 70 years. But only about one half of heritable breast cancers are due to faulty genes. In contrast, 95% of mammary malignancies are sporadic or nonfamilial and do not possess altered BRCA1 or BRCA2 genes. In familial colon cancer, a number of high penetrance genes have been identified, such as APC and hMSH1 and hMSH2, and a model of carcinogenesis with progressive accumulation of genetic and chromosomal anomalies was delineated. However, the proportion
0188-4409/02 $–see front matter. Copyright © 2002 IMSS. Published by Elsevier Science Inc. PII S0188-4409(02)00 3 9 3 - 4
426
Benítez-Bribiesca/ Archives of Medical Research 33 (2002) 425–427
of these inherited colonic cancers in the population is approximately 1–5% in all. Schizophrenia is a frequent and disabling mental disorder affecting almost 1% of the general population. A preponderance of evidence unambiguously shows that heritable factors contribute to the development of the disease. Monozygotic twins of schizophrenics have a 49% chance of being affected, whereas dizygotic twins have only a 14% chance. But the search for the genetic anomaly of this mental disorder has failed to render a conclusive result. Similar efforts to find specific genes for a number of diseases such as rheumatoid arthritis, multiple sclerosis, diabetes, atherosclerosis, obesity, and others have encountered comparable fates (4,5). On the other side of the coin are environmental factors. Molecular genetics by and large ignores the role played by non-genetic factors despite recent efforts to incorporate genetics into epidemiology. It has been conclusively demonstrated that the environment is the major determinant in most diseases. Studies of cancer incidence in immigrants show that after one generation they acquire the local incidence of the malignancy. A change of diet in Pima Indians favors a high incidence of obesity and diabetes. The percentage of coronary heart disease, stroke, diabetes, and colon cancer preventable only by life-style modifications ranges from 70 to 90%. This demonstrates that genome and environment engage in a continuous dialog through which the expression of normal genes can be modulated for good or evil by environmental demands. Based on these observations, it is highly likely that most common human diseases are not attributable to single gene variants (6). They should be viewed as multigenetic, multifactorial, or complex disorders. The naïve view of genetic determinism (that complex traits are caused by a single gene) has progressively been faced in the last decade with the stark reality that nearly all human diseases are complex dependent entities to which our genes make a necessary but incomplete contribution. We now realize that human disease phenotypes are the result not only of faulty genes but also mainly of perturbed self-organizing and lawful networks that display system dynamics (7–9). To the contrary, genomic medicine is based on the reductionistic view that the gene is the ultimate actor of all normal and pathologic human processes and that by mastering the gene, good health and longevity can be achieved. In view of the great promises posed by the prevailing paradigm of genomic medicine, a new industry has emerged and is aimed at developing molecular diagnostic tools and better medicines. Hundreds of biotechnological companies have been established, proposing a cornucopia of new drugs, enough to fulfill virtually every imaginable unmet medical need. Biotechnology industries have attracted many investors, amounting to billions of dollars. Despite sound success in agriculture, bacteriology, and animal genetics, medical applications have been slow to develop and not so successful. There is a litany of drugs against cancer, AIDS, metabolic diseases, and so on that work in the laboratory, whether in
cell cultures or animal models but that are useless in humans because of unintended effects or unanticipated metabolism. Through pharmacogenetics, drug companies have promised to be able in the near future to tailor the right drug for the right patient, a fascinating possibility but quite impractical and costly. Biotechnological industries are not philanthropic enterprises; they are focused on obtaining revenues. For that reason, they are eager to expand sales through marketing strategies highlighting and exaggerating the benefits of their products. Genomic and proteomic tools for diagnosis and risk assessment for many illnesses are now on the market and physicians and patients are being convinced that without them there is no medicine at the frontline. However, even assuming all the benefits of these techniques and the possibility of tailoring drugs for individual patients, their cost would be prohibitive for persons with low income and most importantly, for poor countries. Most common diseases in impoverished societies are infectious, parasitic, and nutritional, and it is well known that they can be effectively controlled by simple cost-effective measures such as running water, sewage, and improved nutrition. Yet millions of dollars are being spent on molecular research for amebiasis, cysticercosis, salmonella, and cholera, but so far these investigations have not produced better means for prevention or control of these diseases. A similar situation has occurred with carcinoma of the cervix, the most frequent cancer in developing nations. Despite the great discovery of human papilloma virus as the causative agent and the formidable effort to uncover all its molecular mechanisms, the old vaginal cytology method continues to be the best method for early detection. What is quite troubling is that biomedical research has not been immune to the commercial trends imposed by industry. Many investigators have been hired by biotechnological industries, and some have established their own companies. Universities and research institutes seek joint ventures with private biotechnological industries to profit from patents for technology or new drugs. Granting that this is a clever strategy to obtain generous funds for the everincreasing cost of biomedical research, there is a hidden danger in that these commercial associations can divert the fundamental quest of a basic scientist, i.e., the search for new knowledge, to the ambitious goal of economic profits. There should be no doubt, however, that the wealth of information that genomic biomedical research has provided for understanding the mechanisms of disease has been impressive and has opened new doors for accurate diagnosis and in some cases for effective treatment. It is the monopoly of the “genocentric” idea in medicine that threatens to cancel other means for understanding the most common diseases, which are by all accounts very complex entities (9– 11). The term “genomic medicine” is misleading because it highlights only the role played by genes in the pathogenesis of disease, casting aside epigenetic, environmental, and social factors. Medicine throughout history was never qualified by prevalent discoveries: at the time of Vessalius one
Genomic Medicine
never spoke of “anatomic medicine”, when Schleiden and Schwann proposed their theory, no “cellular medicine” emerged; Pasteur and Koch did not speak of “bacteriological medicine”, Krebs and Cori did not refer to “biochemical medicine”, after the Bunett and Medawar immunological discoveries medicine did not evolve into “immunological medicine”. Even taking into account today’s modern trend, it would be improper to speak of “complexity medicine”. Medicine needs no adjectives but certainly needs the scientific armamentarium offered by all sciences, including biology, biochemistry, physics, informatics, mathematics, epidemiology and of course, genomics.
References 1. R Chakravarti A. To a future of genetic medicine. Nature 2001; 409:822–823.
427
2. Jiménez-Sánchez G, Childs B, Valle D. Human disease genes. Nature 2001;409:853–855. 3. Aach J, Bulyk ML, Church GM, Comander J, Derti A, Shendure J. Computational comparison of two draft sequences of the human genome. Nature 2001;409:856–859. 4. Zweiger G. Transducing the genome. Information, anarchy, and revolution in the biomedical sciences. New York: McGraw-Hill;2001. 5. Eeles RA, Ponder BAJ, Easton DF, Horwich A. Genetic predisposition to cancer. 1st ed. London: Chapman & Hall Medical;1996. 6. Willet WC. Balancing life-style and genomics research for disease prevention. Science 2002;296:695–698. 7. Rees J. Complex disease and the new clinical sciences. Science 2002;296:698–701. 8. Strohman R. Maneuvering in the complex path from genotype to phenotype. Science 2002;296:701–703. 9. Benítez-Bribiesca L. Complexity: the new frontier in biomedical research. Arch Med Res 2000;31:1–2. 10. Chong L, Ray LB. Whole-istic biology. Science 2002;296:1661. 11. Kiberstis P, Roberts L. It’s not just the genes. Science 2002;296:685.