Dhavendra Kumar, Institute of Cancer & genetics, University Hospital of Wales, Cardiff, UK; Genomic Policy Unit, The University Hospital of Wales, Pontypridd, UK and The Genomic Medicine Foundation (UK).
The natural selection theory for evolution put forward by Charles Darwin had clear overtones reflected in some of our present-day concepts of the genetic basis of biological life. Mendel’s laws of inheritance, and successive discoveries in various aspects of genetics, laid the foundation of Mendelian genetics, a major recognized field within the science of genetics. This subsequently became the cornerstone for human genetics. Several years later the science of genetics is rewarded with the genome era. The future now appears bright, opening up many opportunities on the horizon. Clinical genetics is now a recognized medical specialty among several disciplines comprising the current spectrum of modern medicine. The basis of clinical genetics is grounded in the sound knowledge and understanding of medical genetics which emerged as a spin-off of ‘Human Genetics’.
Fifty years after the discovery of the double-helix structure of the deoxyribonucleic acid [DNA] molecule (Watson and Crick, 1953), characterization of the complete sequence and organization of the human genome was successfully accomplished (Lander et al., 2001; Venter et al., 2001). This major scientific achievement laid the foundation of ‘human genomics’; that section of the biological sciences which studies variations, mutations and functions of genes and controlling regions, and their implications on human variation, health and disease. This is strengthened by developments in the other areas of genomics relating to bacteria, vectors, parasites, animals and plants.
The identification of all human genes and their regulatory regions provides the essential framework in our understanding of the molecular basis of disease. This advance has also provided a firm foundation for the future development of genomic technologies that can be applied to modern medical science. Rapid developments in global gene analysis, gene product analysis, medical bio-informatics, and targeted molecular genetic testing are destined to change the practice of modern medicine (Guttmacher and Collins, 2002). However, many practicing clinicians perceive developments in genomics as primarily confined to the research arena with little clinical applicability. DNA/RNA-based methods of disease susceptibility screening, molecular-based disease diagnosis and prognosis, and genomics-based therapeutic choices and prediction of treatment outcome are some of the key promising areas that have influenced and raised expectations for reforming the practice of modern clinical medicine.
Undoubtedly the science of genomics holds tremendous potential for improving human health. The expert working group convened by the World Health Organization [WHO] has made several recommendations on the scope and application of genomics on global health (WHO, 2002). It is acknowledged that the information generated by genomics will provide major benefits in the prevention, diagnosis and management of communicable and genetic diseases as well as other common medical diseases, including cardiovascular diseases, cancer, diabetes and mental illnesses (Cardon and Bell, 2001). Together these constitute the major health burden, as reflected in chronic ill-health and mortality. In addition, a number of infectious diseases are associated with genomic mutations manifesting in the form of increased susceptibility, clinical severity, desired therapeutic response to anti-microbial therapy and in conferring protection. It is possible that the protective effect of a microbial vaccine might be influenced by genomic variation.
The sequence of the entire human genome is nearly complete but this is not limited to one individual alone . Each person carries a distinct sequence. The variation among all humans is reflected in variation within the human genome. The genomic variation between individuals together with environmental factors probably determines the disease susceptibility, and is important in drug efficacy and side effects (Holden, 2000; Chakravati, 2000). The key to genomic variation lies in finding single nucleotide polymorphisms [SNPs] and its use in disease association studies (Stephens et al. 2001). The positional cloning (identifying the gene by location followed by functional analysis) of the disease susceptibility loci will depend upon the successful application of haplotype associations. In addition, these will be important in clinical studies to find individuals in whom a drug is likely to be efficacious. The use of SNPs in pharmacogenetics is currently restricted to studying genes for drug-metabolizing enzymes, such as P450s, and variations in genes that target drug receptors. The newly emerging dynamic field of pharmacogenomics is an exciting application of genomic variation in drug discovery and drug development.
The recent cloning of real disease susceptibility genes for multifactorial diseases is encouraging, for example, the identification of NOD2 as a susceptibility gene for Crohn’s disease (Hugot et al., 2001 and Ogura et al., 2001). This is a major development in understanding the pathophysiology of inflammatory bowel disease. Similar studies are likely to unravel the genetic mechanisms in other complex medical diseases. A comprehensive SNP map will allow the cloning of other susceptibility alleles. However, this will depend upon population sample and size, the method employed, linkage disequilibrium or association studies rather than the technology used (Cardon and Bell, 2001). Some of the best genetic studies of this kind include susceptibility to infectious disease, for example an association between chemokine receptors (CCR5) and HIV susceptibility, and between the bacterial transporter protein Nramp and resistance to macrophage-infecting bacteria such as Mycobacterium tuberculosis. Similarly, various alleles at the G6PDH locus determine malaria susceptibility (Tishkoff et al., 2001).
These kind of studies and clinical applications of the resulting outcomes are not without ethical concerns. Some of the questions and concerns are related to ownership of the genes and freedom to use collected DNA for such studies. These are complex and emotional issues, especially when dealing with populations who may have been exploited. These issues should always be dealt with carefully under the statutory requirements and rules.
There has been a tremendous surge in various sub-specialties and technologies with names ending in -omics. We are rapidly moving into the “omics” era. In addition to genomics, several new specialist fields with an ‘omics’ suffix have recently appeared, for example, pharmacogenomics, nutrigenomics, metabonomics, transcriptomics, proteomics, micribiomics, glycomics, toxicogenomics, and many more. Whatever the basis of distinction might be, the driver of all these terms is GENOMICS – the study of genomes in its entirety.
Genomics is not just about genome sequencing. Apart from full-length cDNAs and their sequences, copies of mRNAs that actually exist and code for different proteins are probably more important. The study of proteins thus derived falls within the broad field of proteomics, a likely outcome of functional genomics and probably a true companion to genomics. It is likely that eventually proteomics will have more practical applications in clinical medicine. This is rapidly moving ahead with the completion of the HapMap project (Nature, 2005) and the future ‘functional-variant database’, a natural outcome of the HapMap project (Gibbs, 2005).
It is vital that existing gaps in our knowledge about various ‘omics’ disciplines are filled to ensure efficient use of the valuable information emerging from research. It is also important that the gap between ‘genetic professionals’ and the ‘primary-care community, and as well as the ‘public health community’, is narrowed (Khoury et al., 2003). Integration of this knowledge in the medical education curriculum and the continued professional education programs is urgently required to ensure applications of genomics in the provision of healthcare.
During the last two decades, the practice of medical genetics or clinical genetics, has found its niche within the broad horizon of clinical medicine. Genetic services now constitute a small, but albeit important, component of modern medical practice and public health. Currently, genetic services focus on providing information on chromosomal and single-gene diseases with limited contribution to multifactorial/polygenic diseases. How would this then be different from genomics? Already there is tremendous enthusiasm for the recently introduced term of ‘genomic medicine’. In a primer on genomic medicine, Guttmacher and Collins (2002) viewed “genetics as the study of single genes and their effects” and genomics as “the study not just of single genes, but of the functions and interactions of all the genes in the genome.” In simple terms, there is a quantitative difference between the two fields – the study of multiple genes as opposed to one gene. Thus genetics can be seen as part of genomics! However, there is a qualitative difference between genetics and genomics in medical and health applications ranging from the concept of disease in genetics to the concept of information in genomics (Khoury et al., 2003).
The practice of medical genetics has traditionally focused on those conditions that result from specific alterations or mutations in single genes (e.g., inborn errors of metabolism, Duchenne muscular dystrophy, and Huntington’s disease), whole or part of chromosomes (e.g., trisomy 21 in Down syndrome), or associated with congenital malformations and developmental disabilities. The existing model of medical genetic services for these conditions includes laboratory diagnosis, genetic counseling and management. This is supported by public health measures to ensure delivery of genetic services and genetic screening (e.g., new-born screening or screening the high-risk population). On the other hand, the practice of genomics in medicine and public health will focus on information resulting from variation at one or multiple loci and strong interactions with environmental factors, for example diet, drugs, infectious agents, chemicals, physical agents, and behavioral factors (Khoury et al., 2003).
What medical and public health applications could one foresee following the completion of human genome sequence in 2003? How could these be applied and delivered to the 95% of human diseases that do not fall under the rubric of genetic disorders? These are some of the likely questions related to genomic medicine. Medical and public health professionals urgently need to make the changes necessary to accommodate rapid identification and characterization of the numerous genomic variants at multiple loci which increase or decrease the risks for various diseases, singly or in combination with other genes, and with various chemical, physical, infectious, pharmacologic, and social factors (Khoury, 1999). This genetic and genomic information is crucial in assessing the disease susceptibility among healthy individuals, and in personalized primary and secondary prevention planning. Collins and McKusick (2001) stated that “By the year 2010, it is expected that predictive genetic tests will be available for as many as a dozen common conditions, allowing individuals who wish to know this information to learn their risks for which interventions are or will be available. Such interventions could take the form of medical surveillance, lifestyle modifications, diet, or drug therapy. Identification of persons at highest risk for colon cancer, for example, could lead to targeted efforts to provide colonoscopic screening to those individuals, with likelihood of preventing many premature deaths.”
Personalized medicine will encompass not only common medical diseases, but could include a wide range of preventable diseases [www.genovations.com ]. Genetic testing for future disease susceptibility using multiple genomic variants will be possible and affordable with the application of ‘high throughput’ microarrays-based genetic testing.
A wealth of information on genomics is rapidly being acquired with the potential for major impact on human health. However, this data and information is scattered throughout several scientific journals, reviews and state-sponsored reports and bulletins. A clinician or health professional often has difficulty in accessing and assimilating this information for application in the medical and public health practice. More importantly, an inability to assimilate and interpret leads to frustration and avoidance of potentially useful information. This article sets out the subject from the historical progress to general aspects of genomics and the describing in some detail the medical and health applications.
Exciting new developments in biotechnology and bioinformatics have opened unimaginable horizons that were inconceivable only few years ago. The talk of the next generation sequencing (NGS) is not restricted to the bench of few interested post-doctoral level and young investigators. It is evident everywhere and is now firmly engrained in minds and souls of genetic and genomic researchers, clinicians and health professionals. A number of genetic diseases or group of rare disorders can now be investigated with confidence using multi-gene NGS panels reducing the time in making an accurate diagnosis and helping the clinician to plan focussed clinical investigations and management. Further, many undiagnosed or poorly defined conditions and complex clinical cases can now be investigated using powerful genome technologies, notably the comparative array genomic hybridisation (array CGH), whole exome sequencing (WES) and even whole genome sequencing (WGS), albeit with limited outcomes (Berg et al., 2011; Biesecker and Green, 2014). The focus has shifted from finding the pathogenic sequence variations to functional importance of genome level changes. Unravelling of the complexities of the RNA molecules has made a huge impact in molecular and experimental biology, the basis for transcriptomics (Xa et al., 2014). In addition, challenging and controversial stem cell genomic research has captured the headlines with promises and expectations of massive proportions, notably for neurodegenerative disorders (Lindvall, 2004). Targeting specific segments of the gene using the oligonucleotide skipping technique has raised expectations for treating a number of Mendelian genetic conditions (Goodchild, 2011). This is truly the beginning of the promising phase for applied and translational genomics.
The enormous genomic data and information generated by genome wide association studies (GWAS), deciphering the complex phenotypes by copy number variations and single nucleotide polymorphisms and applying knowledge gained from genetic and genomic analysis in rare Mendelian disorders have offered fine molecular understanding of the underlying pathogenic mechanisms. There is lot of enthusiasm for applying next generation sequencing methods (alongside the Sanger sequencing) in new gene discoveries, unravelling novel molecular mechanisms and identifying critical focal points in molecular pathways in designing and developing targeted molecular therapy models.
Several major global initiatives are being pursued to curate and annotate enormous genomic data and information from new genomic technological advances. The common theme is genotype-phenotype correlation. Leaders in this approach include the Human Variome Project (www.humanvariomeproject.org), Gen2Phen project (www.gen2phen.org) and recently launched Human Phenome Project (Freimer and Sabbati, 2003). Successful outcomes of these projects might offer clarification and evidence that could be applied in medicine and health. However, there is sufficient evidence around supporting the argument for genomic applications for enhancing the diagnostic and probably the prognostic potential of genomic medicine and health. Promising new therapeutic developments have followed, particularly discovery and development of new drugs and pharmacogenetic / pharmacogenomics evidence necessary for personalised pharmacotherapy.
So how do genomics and all related genome technologies impact upon Medicine and Health? Do we have enough data, understanding and robust evidence to apply and translate in practising effective and efficient clinical medicine? We are probably safe to gently move in the next phase of the genomic and personalized medicine. Has genome sequencing done any good to human health? Francis Collins believes that ‘I think there are people who’s lives have been saved because of the study of the genome.’
Genomic medicine and health genomics is a global phenomenon. Prospects of this major revolution are enormous and unimaginable. Skeptics argue that this is all disproportionately overhyped. Nevertheless massive investments in all parameters are poured into this field globally with sky-high promises and huge expectations. A major global alliance has committed itself to bring all geneticists, genome scientists, genome technology experts, genetic clinicians and health genomic experts together for the benefit of global health (www.genomeandhealth.org)
Perhaps, it is most relevant at this juncture to remind us that the practice of Medicine is an art based on sound scientific principles. It would be appropriate to quote Sir William Osler’s remarks, “If there were no individual variability, medicine would have been science not an art.” Genomics in this context provides the basis of individual variability and the modern genomic era clinician will need to ensure that this continues to be applied as an art.
Berg, Jonathan, Muin J Khoury and James P Evans (2011).
Deploying whole genome sequencing in clinical practice and public health: Meeting the challenge one bin at a time. Genetics in Medicine (2011) 13, 499–504;
Biesecker , LG and Robert C. Green, (2014)
Diagnostic Clinical Genome and Exome Sequencing. N Engl J Med 370:2418-2425
Cardon, LR and Bell, JI (2001) Association study designs for complex diseases. Nat. Rev.Genet. 2:91-99.
Chakravati, A (2000): To a future of genetic medicine. Nature 409: 822-823.
Collins FS, Guttmacher AE (2001): Genetics moves into medical mainstream. JAMA 286:2322-2324.
Collins FS, McKusick VA (2001): Implications of the Human Genome Project for medical science. JAMA 285:540-544.
Freimer, Nelson & Sabatti, Chiara (2003).
The Human Phenome Project. Nature Genetics 34:15-21.
Genovations – the advent of truly personalized healthcare. http://www.genovations.com
Gibbs R (2005): Deeper into the genome. Nature 437:1233-1234.
Goodchild J (2011). Therapeutic oligonucleotides. Methods Mol Biol. 764:1-15.
Guttmacher AE, Collins FS (2002): Genomic medicine: A primer. N Eng J Med 347:1512-1520
Holden, AL (2000): The SNP consortium: A case study in large pharmaceutical company research and development collaboration. J Com Biotech 6:320-324.
Hugot, JP et al. (2001): Association of NOD2 leucine-rich variants with susceptibility to Crohn’s disease. Nature 411:599-603.
Khoury MJ (1999): Human genome epidemiology: translating advances in human genetics into population-based data for medicine and public health. Genet Med 1:71-73.
Khoury MJ, NcCabe LL, McCabeER (2003): Population screening in the age of genomic medicine. N Eng J Med 348:50-58.
Lander, ES et al. (2001): Initial sequencing and analysis of the human genome. International Human Genome Sequencing Consortium. Nature 409:860-921.
LINDVAL,O,, ZAAL KOKAIA2, 3, 5 & ALBERTO MARTINEZ-SERRANO(2004).
Stem cell therapy for human neurodegenerative disorders–how to make it work. Nature Medicine 10, S42–S50 (2004)
Nature (2005): A haplotype map of the human genome- Report from the International HapMap Consortium. Nature 437:1299-1320.
Ogura, Y et al. (2001): A frameshift in NOD2 associated with susceptibility to Crohn’s disease. Nature 411: 603-606.
Stephens, C et al. (2001): Haplotype variation and linkage disequilibrium in 313 human genes. Science 293: 489-493.
Tishkoff, SA et al. (2001): Haplotype diversity and linkage disequilibrium at the human G6PDH: recent origin of alleles that confer malarial resistance. Science 293: 455-461.
Venter, JC et al. (2001): The sequence of the human genome. Science 291:1304-1351.
Watson, JD and Crick, FHC (1953): Molecular structure of nucleic acids. Nature 171:737-738.
World Health Organization (2002): Genomics and World Health- Report from the Advisory Committee on health research. WHO,Geneva.
Integrative clinical transcriptomics analyses for new therapeutic intervention strategies: a psoriasis case study. Drug Discov Today. 19(9):1364-71.