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PII: S0735-1097(00)00776-2

  1. 1. A perspective: the new millennium dawns on a new paradigm for cardiology—molecular genetics Robert Roberts J. Am. Coll. Cardiol. 2000;36;661-667 This information is current as of July 22, 2010 The online version of this article, along with updated information and services, is located on the World Wide Web at: http://content.onlinejacc.org/cgi/content/full/36/3/661 Downloaded from content.onlinejacc.org by on July 22, 2010
  2. 2. Journal of the American College of Cardiology Vol. 36, No. 3, 2000 © 2000 by the American College of Cardiology ISSN 0735-1097/00/$20.00 Published by Elsevier Science Inc. PII S0735-1097(00)00776-2 REVIEW ARTICLES A Perspective: The New Millennium Dawns on a New Paradigm for Cardiology—Molecular Genetics Robert Roberts, MD Houston, Texas Western civilization had two great epochs—the sixth century B.C. and the 18th century. The 21st century is likely to be the third great epoch. Although cardiology has advanced more in the last 50 years than in the previous 2,000, it is likely to advance more in the next two or three decades than in the previous 2,000 years, including those 50 golden years. The engines of ingenuity to provide the thrust for the 21th century will come from molecular genetics and the application of recombinant deoxyribonucleic acid (DNA) techniques. Identification of all human genes (50,000 to 100,000) in the next two to three years will help link thousands of etiologies and risk factors with their respective diseases, which represents a new paradigm in medicine. This is illustrated by the implications to be drawn from familial hypertrophic cardiomyopathy and the 50 new genes already identified to be responsible for cardiac disease. The hope for prevention and treatment of human disease is unprecedented. Twenty diseases account for 80% of the deaths in the Western world and are due to 100 to 200 genes, all of which will be available in a couple of years. The Phoenician alphabet (inclusive of the Greek vowels) of 26 letters launched two millenniums of Western civilization, whereas the DNA alphabet of only four letters will launch and dominate the next millennium. (J Am Coll Cardiol 2000;36:661–7) © 2000 by the American College of Cardiology Western civilization is noted for two great epochs—namely, by Captain Cook, on reaching Australia in 1770 (3): “Not the 6th century B.C. and the 18th century A.D. 4859 (1). only have I traveled farther than any man has traveled, but The high level of conceptual thinking of the Greeks in the I have traveled as far as man can travel.” There is little doubt 6th century B.C. led to the birth of Western philosophy and that the 6th century B.C. molded our society for the next democracy from which evolved the foundations of Western two millenniums, and the Industrial Revolution of the 18th civilization. The widespread use of the phonetic alphabet is century continues to improve the living conditions of all arguably a major factor that contributed to the success of the mankind. A comparable timeline for the history of medicine 6th century B.C. The alphabet (defined as one with 30 starts in Greece on the island of Cos with Hypocrates, the symbols), claimed to be developed by the Semites (Phoene- founder of modern medicine. The Greeks pursued medicine cian), had no vowels. There were written languages be- with great intensity, but throughout the Dark Ages and the fore—namely, hieroglyphics (Egyptians), cuneiform (Sum- Christian and Islamic religious eras, when medicine expe- erians) and Chinese characters— but these were all pictorial rienced some significant advances, for the most part, science and emphasized concrete thinking. The alphabet, with its was stifled. Evolution of reason and scientific thought after symbols, was simple and stimulated abstract thinking. The the Renaissance restored a progressive approach to science addition of the vowels, probably between the 9th and the and medicine. Nevertheless, just over 60 years ago (1931), 6th century B.C. by the Greeks, is thought to have signif- Paul Dudley White boldly stated there was no effective icantly facilitated the translation from the spoken to the treatment for valvular disease, coronary artery disease, hy- written world. It is well recognized that translating the pertension or syphillis (4). In the 1940s, sulfonamides and spoken word into the written word of Indo-European penicillin were introduced, followed by an explosion that languages is very difficult without vowels (2). The 18th ushered in the modern era of cardiology. Cardiology has century brought the Industrial Revolution, a uniquely West- without doubt advanced more in the last 50 years than in the ern contribution, which started us on the road to modern previous 2,000 years. Today, the heart is just another work technology and has continued at an accelerating rate. From place we invade with a variety of tools such as the coronary the 15th to the 18th centuries, European explorers took catheter, the angioplasty catheter, bypass grafts, pacemakers Western civilization to all corners of the Earth, as remarked and a host of others. Their application, along with preven- tive medicine, in the past 30 years has resulted in an From the Section of Cardiology, Baylor College of Medicine, Houston, Texas. astounding 60% reduction in the death rate from heart This work is supported in part by grants from the National Heart, Lung, and Blood Institute of the National Institutes of Health (Bethesda, Maryland), Specialized disease (5). It is reasonable to assume the 21st century will Centers of Research (P50-HL54313-01-01), the National Institutes of Health be the third great epoch for our civilization, and it is likely Training Center in Molecular Cardiology (T32-HL07706) and the American Heart to be evident in the next 20 to 30 years, as I believe Association, Bugher Foundation Center for Molecular Biology (86-2216). Manuscript received November 24, 1999; revised manuscript received April 1, cardiology will advance more in the next two to three 2000, accepted April 11, 2000. decades than it has in the previous 2,000 years, including Downloaded from content.onlinejacc.org by on July 22, 2010
  3. 3. 662 Roberts JACC Vol. 36, No. 3, 2000 The Millennuim Dawns on a New Paradigm for Cardiology September 2000:661–7 including the genes, by the year 2005. Commercial efforts Abbreviations and Acronyms announced that all of the human genes would be sequenced ACE angiotensin-converting enzyme by the year 2001 (8,9). The Human Genome Project has ARVD arrhythmogenic right ventricular dysplasia also been progressing more rapidly than expected. It was AT-1 angiotensin one predicted that half of the human genome would be com- DNA deoxyribonucleic acid EST expressed sequence pleted by the year 2001 and the remainder by 2003 (10). FDCM familial dilated cardiomyopathy More recently, with the boost in funding for the three major FHCM familial hypertrophic cardiomyopathy U.S. players (Baylor College of Medicine, Washington HCM hypertrophic cardiomyopathy University and The Whitehead Foundation), it is predicted that a rough draft of 90% of the human genome will be available by March 2000 (11). that great golden age of the last 50 years. The engines of The new paradigm for cardiology and medicine— ingenuity to provide the thrust for the 21st century will etiologic and individualized treatment. Despite our come from molecular genetics and the application of recom- knowledge of diagnosis and treatment, we seldom know the binant deoxyribonucleic acid (DNA) techniques. etiology or the specific molecular defect responsible for In the 20th century, man has mapped the earth, its oceans disease, and thus our therapies are not as specifically and explored its inner composition. We have experienced targeted as one would desire. In the next couple of years, the excitement of the gold rushes and the oil gushes and regardless of when the Human Genome Project is com- characterized Earth’s precious gems and metals. We have pleted, there will be at least 30,000 genes available, and thus seen the development of the physicist’s table of elements we will have thousands of etiologies and specific molecular that in turn led to many exciting innovations. The 21st defects to be linked with their respective disease. This will century will be ushered in by the new science of molecular represent an entirely new paradigm in the field of medicine. biology, based on the fundamental units of mankind that are Similarly, in the field of preventive medicine, there will be responsible for passing on all of the inheritable characteris- thousands of genetic risk factors that will need to be tics—DNA. For the first time, the biologist and the matched with diseases for which they are predisposed. We, physician will march together with their complete table of as physicians, are taught to treat the crisis, and until the elements, and it will not be a list of inorganic components 1990s, physicians who saw and treated a high percentage of but rather the 50,000 to 100,000 genes responsible for one normal individuals were considered perhaps to be nondis- human. Knowing the genes and their functions will have criminatory in applying the art of medicine. Prevention will universal appeal and invoke interest from all phases of be the key to future successes, and the unraveling of human medicine, science, philosophy, ethics, the arts and govern- genes will catapult prevention as a major initiative for the ment—it will be as Francis Collins has stated, a “code for 21st century. In the management of coronary artery disease, the book of life” (6). The DNA code uses four letters: A individuals will be identified in their teens so that treatment (adenine), G (guanine), C (cytosine) and T (thymine). and prevention appropriate for their medical risk profile and These letters are strung together into distinct units referred life style can be properly individualized. Treating coronary to as genes, which give rise to a unique protein destined for artery disease after the crisis of myocardial infarction, when a distinct morphologic location and function within the a part of the myocardium has already been lost to scar, will human body. These proteins are responsible for every action be seen in the 21st century as negligent and a missed that a human being performs. Thus, most of what we do and opportunity. It is evident from present day knowledge that how we do it is strongly influenced by the sequence of these four primary prevention of atherosclerosis is far more effective letters. The Phoenecian alphabet (inclusive of the Greek than treating acute myocardial infarction. The massive array vowels) of 26 letters launched more than two milleniums of of specific etiologies and risk factors will be truly staggering, Western civilization, whereas the DNA alphabet of only and it is for this reason that all of us as physicians must at four letters will launch and dominate this millennium. least become acquainted with the new terminology. The Although progress will continue on the inner structure of area of pharmacogenomics (12), although now only in its the Earth and great strides are likely to be made in exploring infancy, will rapidly evolve in the next 10 years. Individu- our galaxy, the hallmark of the 21st century will be the alization of therapy, the antithesis of health maintenance exploration of the inner workings of a human being. To use organizations and managed care, will be the norm. a phrase from the old millennium: “Your genes will be up in Angiotensin-converting enzyme (ACE) inhibitors may be your face.” more effective than angiotensin one (AT-1) receptor block- The human genome, contained in 23 chromosomes, ade for the hypertensive patient who has expressed a consists of three billion bases with an estimated 50,000 to vulnerable polymorphism in the ACE, whereas the latter 100,000 genes. The genes (made of exons) make up about might be more appropriate for those with an expressed 3% of the DNA, and the in-between sequences (introns) vulnerable polymorphism in the AT-1 receptor. Because the have an unknown role so far. The Human Genome Project, genes present in the DNA of a white blood cell are identical to initiated in 1990 (7), was to sequence all of the DNA, the genes in the cell of any other organ (brain, heart, etc.), these Downloaded from content.onlinejacc.org by on July 22, 2010
  4. 4. JACC Vol. 36, No. 3, 2000 Roberts 663 September 2000:661–7 The Millennuim Dawns on a New Paradigm for Cardiology genetic etiologies and risk factors responsible for diseases can be (ARVD). Several genes have been identified in the mito- detected from analysis of a single blood sample (13). The chondrial DNA to be responsible for cardiomyopathies development of DNA as a computerized chip will make it (23). Genes have also been identified as responsible for possible to screen for thousands of mutations within a few ventricular arrhythmias, supraventricular arrhythmias, con- hours. It was realized very early in the genetic revolution duction disorders, anatomic defects (septal, aortic) and that there would have to be a new science (bioinformatics) neuromuscular disorders affecting the heart (see review in to store and retrieve such massive information. A comput- [19]). In addition, several genes that cause lipid disorders, erized network of gene banks was established in London, hypertension and various vascularopathies have been iden- Washington and Tokyo and made available to PC users tified. Many other genes present in the invertebrate and throughout the world. The GenBank has stored over two vertebrate heart have been identified and shown to play a billion bases of DNA from 39,000 species (6) and 1,000 major role in the development of the heart, which will genes with 20,000 mutations known to cause human disease accelerate the finding of their analogues in the human heart (14). The establishment of computer terminals at nursing (24). The genetics of cardiac development is progressing in stations throughout hospitals will provide access to the simpler organisms such as the zebra fish and the chicken computerized gene data bases so that genetic information is embryo and from genes identified as responsible for inher- immediately accessible to the clinician and paramedical ited cardiac developmental defects. These pathways of personnel. investigation will merge and accelerate the identification of Progress in cardiovascular genetics. Until recently, it was genes responsible for early cardiac development, while at the possible to identify only genes responsible for disease if one same time they will provide fundamental insight into knew the specific protein, whereas today, by using a tech- understanding the cardiac growth response. nique of genetic linkage analysis to map the chromosomal Familial hypertrophic cardiomyopathy as an illustrative location of the gene and positional cloning, one can identify example of genetics for the 21st century. Familial HCM, the gene without knowing the molecular nature of the an autosomal-dominant disease, is the most common cause defect or the responsible protein (15). The ultimate goal of of sudden death in the young, particularly in the athlete. the Human Genome Project was to sequence the human Familial HCM is more common than realized, occurring genome; however, other important objectives were com- with an incidence of one in 1,000 in the population. It is pleted along the way. A genetic map was developed with associated with cardiac myocyte and filament disarray, over 6,000 chromosomal markers placed throughout the hypertrophy and increased fibrous tissue (25). This is a human genome at intervals of less than one million bases. disease that represents a paradigm of the hypertrophic This revolutionized the mapping of the chromosomal loca- response of the heart to injury. The heart adapts to injury, tion (locus) of disease-related genes. The success of genetic whether physiologic or pathologic (e.g., pressure or volume linkage analysis is directly proportional to the quantity and overload), through one of two growth responses—namely, quality of the markers available to map the chromosomal hypertrophy or dilation, or both (26). Familial HCM location of a gene. The development of the genetic map represents the hypertrophic response, whereas FDCM rep- made it possible in a three-generation family to map a locus resents a paradigm of the dilated form. It remains to be in months to weeks as opposed to several years. The other determined whether cardiac dilation is a growth response. It objective was the tagging of unique expressed sequences has been postulated that it is a normal growth response in (EST) with the hope that each tag would represent a which the sarcomeres are added in sequence as opposed to distinct gene. A map of over 40,000 ESTs has been in parallel (in hypertrophy); however, it could represent an developed, which, in conjunction with the list of genes impaired growth response (27). In athletes, the response already mapped, has rapidly accelerated identification of consists of hypertrophy and dilation and returns to normal genes responsible for disease (16). The first primary cardio- with cessation of exercise, suggesting that both responses are myopathy to succumb to genetic linkage analysis was famil- normal. However, it has not been shown morphologically ial hypertrophic cardiomyopathy (FHCM) (17), and beta- that sarcomeres are formed in parallel in athletes. The myosin heavy chain (beta-MHC) was shown to be the hypertrophy of FHCM, although eccentric in 80%, often responsible gene (18). In 10 years, there has been an becomes concentric but is almost exclusively in the left avalanche of genes associated with a variety of diseases of ventricle, with 5% involving the right ventricle. The first the heart. Over 50 genes known to cause heart disease have gene identified to be responsible for FHCM was beta- been mapped to their chromosomal location (19). Eight MHC at 14q1 (17). Since that time, there have been six genes responsible for HCM have been identified with over other genes identified—troponin T, tropomyosin C, tropo- 100 mutations. Although nine loci have been identified nin I, myosin-binding protein C and the two myosin light (mapped) as responsible for familial dilated cardiomyopathy chains (28). Although there are other genes to be identified, (FDCM), only two genes have been identified—actin (20) experience with genotyping new families with FHCM and desmin (21). Four loci (22) have been identified as suggests that most of them are due to one of the known responsible for cardiomyopathies of the right ventricle— genes. On the basis of our data base of over 3,000 individ- namely, arrhythmogenic right ventricular dysplasia uals with FHCM, the beta-MHC gene accounts for 50% Downloaded from content.onlinejacc.org by on July 22, 2010
  5. 5. 664 Roberts JACC Vol. 36, No. 3, 2000 The Millennuim Dawns on a New Paradigm for Cardiology September 2000:661–7 of the patients, and myosin-binding protein C together with troponin T accounts for another 30%; the results published by Seidman et al. (29) are similar. Thus, it is likely the seven known genes are responsible for 80% to 90% of FHCM. It is important to emphasize that essentially all of the cases of HCM (excluding those with known acquired causes) have a genetic basis, but some are sporadic rather than familial. Of course, once a sporadic de novo mutation occurs, it is highly likely to become familial in the next generation, although mutations with very low penetrance may not be expressed in all generations. There are over 100 mutations now identified in the seven genes responsible for FHCM, and most are due to a single base substitution that results in the substitution of one of the amino acids; however, a few are due to small deletions or insertions. From genotype–phenotype correlations, it is rare to observe any clinical, electrocardiographic or echocardio- Figure 1. Kaplan-Meier survival curve showing the correlation between the graphic features of FHCM before puberty (30 –33). Rare incidence of sudden death and the type of mutation (35,36). This shows that patients with the Arg4033 Gln mutation have an average life span of cases have been observed before puberty, but they probably 28 years as compared with an average life span into the 60s with the are homozygous from both parents having the disease. The Glu9303 Lys mutation. lack of disease before puberty provides an important time window for prevention when such therapy becomes avail- 28 years, whereas the mutation Glu9303 Lys, Arg3249- able. After puberty, the age of onset is highly variable, and, Gln has a life span of 43 years, and Leu9083 Val, as stated previously, in HCM due to the myosin-binding Val6063 Met, Cly2563 Glu of 62 years. It should be protein C gene, onset may not occur until the fifth or sixth emphasized that while certain mutations appear to be decade of life. Second, the presence or absence of clinical predictive, other factors are very important—namely, inter- features, even within the same family, is highly variable. actions with other genes and environmental stimuli. These Third, the incidence of sudden death is highly variable and factors hopefully will be elucidated and shown to explain the does not correlate with the presence or severity of any of the variation that occurs in the phenotype of this disease, even clinical features. In patients with FHCM due to troponin T within the same family with the same mutation. The mutations, there is very little cardiac hypertrophy but a high importance of environment on expression of the mutant incidence of sudden death (34). In patients with FHCM gene is amply illustrated by FHCM, in which the disease is due to mutations in the beta-MHC gene, there is consis- seldom seen in the right ventricle despite the mutant gene’s tently hypertrophy, but the incidence and frequency of presence in equal abundance in the right and left ventricles. sudden death are highly variable. Last, several studies by This is similarly illustrated in ARVD, in which the disease several investigators have shown a strong correlation be- is present primarily in the right ventricle. Gene-to-gene tween the incidence of sudden death and the type of interaction is emphasized by the observation that FHCM mutation (32,35,36). This is illustrated in Figure 1, which mutations occurring in individuals with the DD allele of the shows that patients with the Arg4033 Gln mutation have ACE genes have more extensive hypertrophy and a higher an average life span of 28 years compared with an average incidence of sudden death. Because the genes present in the life span into the 60s with the Glu9303 Lys mutation (37). DNA of a white cell are identical to those in the heart or brain, In a collaborative study with Seidman’s group, we observed a blood sample provides immediate access to all genes (39). an interesting correlation between age of onset of the disease Thus, a new era will dawn with the ability to genotype for and mutations in the myosin-binding protein C (38). The all diseases; a specific diagnosis can be made using a single analysis consists of 16 unrelated families with a total of 574 blood sample, enabling a rational basis for their prevention members; we found 12 novel mutations, with 212 affected and treatment. It is awesome and scary to realize that a individuals. The onset of the disease was very age depen- single blood sample will provide the specific etiology of dent, with many individuals exhibiting no manifestations of thousands of diseases. In the near future, as we learn more the disease until they were in their fourth or fifth decade of about factors that affect gene penetrance and expression, life. This finding is relevant to the so-called HCM of the genotyping will provide not only a more specific diagnosis, elderly, which is assumed to be an acquired disease but may but also a basis to risk, stratify, and select more appropriate be genetic with expression in the seventh or eighth decade. individual therapy. In summary, only the mutations correlate with the incidence Genetic surprises. As more and more genes become avail- of sudden death. On the basis of the observation of a large able, it is highly likely that many defects not previously number of families, we have observed that Arg4033 Gln, considered to have a familial origin or disposition will be Arg4533 Crs, Arg7193 Trp predict an average life span of shown to have a genetic component. One example of this is Downloaded from content.onlinejacc.org by on July 22, 2010
  6. 6. JACC Vol. 36, No. 3, 2000 Roberts 665 September 2000:661–7 The Millennuim Dawns on a New Paradigm for Cardiology atrial fibrillation (AF), which hitherto was regarded as an ary to the impaired myocyte contractility induced by the acquired disease. In 1996, we identified a family with early mutant protein. The growth factors responsible for the onset of AF and mapped the genetic defect to chromosome myocyte hypertrophy appear to be different from those 10q22 (40). The disease is inherited as autosomal dominant responsible for fibroblast proliferation, as judged from the and is probably far more prevalent than expected, since over results in these two models. In the rabbit, both hypertrophy 100 families have been identified and loci heterogeneity has and fibrous tissue are increased, whereas in the mouse, it is been demonstrated (41). In Italy, ARVD is a disease that is primarily fibrous tissue, and thus it might be possible, the most common cause of sudden death in the young. It utilizing the two models, to distinguish through subtraction initiates in the right ventricle and only much later in life hybridization between the genes responsible for these two does there appear to be left ventricular involvement. Does growth responses. Isolation of the responsible growth factor this mean there is a chamber-specific gene? Or does it mean for each or both will undoubtedly lead to the development that a stimulus specific for the right ventricle interacts to of specific therapies that can be used to induce growth (e.g., develop this phenotype? It is more likely the latter because after myocardial infarction) or inhibit it (e.g., FHCM). other cardiomyopathies that develop in the left ventricle Given the window of opportunity that exists for most seldom involve the right ventricle, even though the defective autosomal-dominant diseases—namely, years to decades gene is equally abundant in the right ventricle. Three loci before the development of the disease (e.g., FHCM)—a have been mapped responsible for ARVD (42– 44) in variety of agents can be assessed to determine their benefi- families from the Veneto region in Italy and in another cial effect in animal models of genetic disease. Several family in Greece (44). In 1998 (22), a gene was mapped to animal models of FHCM have been generated, and studies chromosome 3p23, responsible for ARVD in a family from are ongoing to assess drugs such as ACE inhibitors to delay North America, and a second locus to 10p12 (45). It now or attenuate the hypertrophic response. It is estimated that appears that ARVD may account for up to 15% of sudden the human heart renews itself about every three weeks, and deaths in the young in North America (46). in the hypertrophic heart, that also includes the fibroblast Genetic animal models and inherited human disease— and its matrix. Thus, if the mutant gene could be inhibited the hope for functional genomics and improved therapy. and the myocardium renews itself by utilizing the normal The excitement and challenge for the next few decades will gene, one would expect a new and normal heart in four to be in determining the function of the genes. At present, we five months. The technology to test this hypothesis in have the ability to identify about 2,000 proteins, so we are animal models in which the expressed mutant gene can be missing only 48,000 to 98,000. In a symposium held in Cold turned off after the development of the phenotype appears Spring Harbor, we estimated that if 15 mouse clinics were to be on the horizon. If the results of such studies show that established in the U.S. and one gene was knocked out each the FHCM phenotype, with its morphologic and functional week, it would take 77 years to identify the function of the abnormalities, is reversible, it will provide a great impetus unknown genes (47). The physician investigator is facing a for the development of therapies designed to inhibit expres- very bright future. Relating the phenotype of inherited sion of the mutant gene. diseases and physiologic functions observed at bedside to The GenBank (referred to earlier) will also play a major their responsible gene(s) will markedly accelerate functional role in functional genomics. In parallel to the sequencing of genomics. There has never been a more exciting and the human genome, several small genomes of single cells are opportune time for the physician investigator; molecular also being sequenced. The first genome to be completely genetics is the preeminent field for translational research. sequenced, and all of its genes identified, was Haemophilis Gene transfer into cultured cardiac myocytes (48,49) or influenza in 1995 with 1.4 million bases. Since 1995, over 40 into germ lines to induce transgenic animals (50 –53), or single-cell organisms have been sequenced, including the large elimination of genes through homologous recombination organism Saccharomyces cerevisiae with a genome of 12 (knockouts), remain the prime methods to elucidate the million bases. This paved the way for the development of molecular basis for disease. Such experiments have been novel antibiotics targeted to specific genes. However, the performed with the human mutant beta-MHC and tropo- most significant development occurred at the end of 1998 nin T genes, and the resulting phenotype is similar to the with the sequence of C. elegans (55). This is the first FHCM phenotype observed in humans. It is of interest that multicellular organism for which the genome has been the mutant beta-MHC gene or troponin T gene induces in sequenced; it has 97 million base pairs and 19,000 genes, transgenic mice a phenotype of myocyte disarray, increased one-fifth the number of human genes. Furthermore, a fibrous tissue, impaired systolic and diastolic function and significant percentage of the genes identified are identical to sudden death, but minimal hypertrophy. In contrast, trans- those of human genes. In C. elegans, all 959 cells that make genic rabbits generated using a human mutant beta-MHC up this tiny worm have been recognized, and because of its gene exhibit all of those features and also significant transparent skin, it is possible to observe the development of hypertrophy (54). On the basis of a variety of animal studies this organism and determine the function of each gene and and certain clinical observations, it would appear that the its morphologic phenotype (56). Although humans may myocyte hypertrophy and fibroblast proliferation is second- have up to 100,000 genes, it is highly likely that many of Downloaded from content.onlinejacc.org by on July 22, 2010
  7. 7. 666 Roberts JACC Vol. 36, No. 3, 2000 The Millennuim Dawns on a New Paradigm for Cardiology September 2000:661–7 these genes belong to families with common consensus motifs Blood Institute of the National Institutes of Health (Be- that share a specific similar function. An example of this would thesda, Maryland) has proposed a new goal under the term be kinases, which transfer high energy phosphate from one “restorative biology” to grow human organs (heart, lung and molecule to the other, a common process throughout the body. brain) over the next 10 years. Gene therapy for solid organs There are over 3,000 genes that encode kinases, but all of those has not yet been effective, but the ease of ex vivo gene uptake have in common a sequence motif and the function of into organs such as veins for bypass grafts or the explanted transferring high energy phosphate. The development of the heart for transplantation into the donor makes this a likely gene bank of different genes from different species now makes success in the near future. We now know that 20 diseases it possible to travel back about one billion years in time. This account for 80% of the deaths in the Western world, and it will help tremendously in determining the function of genes. A is reasonable to assume that only about 100 to 200 genes are DNA sequence of unknown function can be aligned to a DNA involved in these diseases. All of those genes will be sequence in the gene bank from other species. If the function available in a couple of years, and the implications of genetic of the sequence is known in another species, a similar function screening for prevention or of new therapies resulting from will most likely prevail in humans. It will also play a large role targeted development are enlightening and staggering. The in understanding evolution, this time at the molecular level— implications of the human genome for the prevention and namely, the gene that has been altered—rather than studying treatment of disease are greater than we can imagine. It was the evolutionary change expressed through the phenotype. once postulated that our genes would all be on a CD-ROM A look into the future. The Human Genome Project has and available during an interview, such as for employment been compared to that of the Apollo or the Manhattan by the year 2030; this is now possible by 2008. There could Project. The impact of the Human Genome Project, in my be some casualties, as occur with any revolution, and thus opinion, is likely to be far greater than that of either the bioethical considerations must proceed along with the Apollo or the Manhattan Project. The technology to geno- scientific discoveries (58). Despite the concerns, the proper type thousands of mutantions through use of technology application of these techniques should affect a marked such as the DNA chip or mass spectrometry is progressing reduction in human suffering from disease, and it has been rapidly and promises to have an assay turnaround time of predicted that human life span will be prolonged by at least hours. This will make available all of the human genes and 50% in the next millennium. their variants. Development of this technology and the completion of the human genome will provide clinical Acknowledgments access to thousands of genetic risk factors and specific I thank Dr. James Watson, who inspired me to write this on etiologies. Genotyping for gene variation will provide a new a recent visit to Cold Spring Harbor, and Dr. Leroy Hood, era for selecting appropriate drugs (pharmacogenetics). For who stimulated many of these ideas. I greatly appreciate the example, a hypertensive individual with the DD form of the secretarial assistance of Debora Weaver and Debbie ACE gene would more likely respond to an ACE inhibitor, Graustein in the preparation of this manuscript and figures. whereas someone with a gene variant causing increased catecholamines would more likely respond to a beta- Reprint requests and correspondence: Dr. Robert Roberts, blocker. The elucidation of the pathogenesis of disease in Section of Cardiology, Baylor College of Medicine, 6550 Fannin, genetic animal models provides specific molecular targets MS SM677, Houston, Texas 77030. for drug development. The target is not just the defective molecule inducing the disease, but also the additional REFERENCES targets upstream and downstream from this molecule, which comprise the pathway of signaling proteins and other 1. Van Doren C. A History of Knowledge: Past, Present, and Future. necessary substrates. 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  9. 9. A perspective: the new millennium dawns on a new paradigm for cardiology—molecular genetics Robert Roberts J. Am. Coll. Cardiol. 2000;36;661-667 This information is current as of July 22, 2010 Updated Information including high-resolution figures, can be found at: & Services http://content.onlinejacc.org/cgi/content/full/36/3/661 References This article cites 43 articles, 20 of which you can access for free at: http://content.onlinejacc.org/cgi/content/full/36/3/661#BIBL Rights & Permissions Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://content.onlinejacc.org/misc/permissions.dtl Reprints Information about ordering reprints can be found online: http://content.onlinejacc.org/misc/reprints.dtl Downloaded from content.onlinejacc.org by on July 22, 2010