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Editorial Indian Pediatrics 2003; 40:607-611 |
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Implications of Human Genome Project for Pediatric Practice |
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Editor’s note: The article is based on presentation at ‘Indo-UK Symposium’ on Hot Topics in Pediatrics, held on 1st -2nd February, 2003 at New Delhi.
As genetic disorders are commoner in children, major impact of HGP will be felt in the practice of pediatrics. Direct benefits that will accrue from the HGP will be: (i) Identification and cloning of more and more new genes, ranging from those for genetic disorders to those for asthma, growth, and obesity; (ii) Precise diagnostic tests for genetic disorders; (iii) Prenatal diagnosis to reduce the burden of various disorders; (iv) Identification of genes that are either directly responsible or predispose to common disorders like heart disease, spina bifida, congenital heart disease, hypertension, diabetes mellitus, etc.; (v) Greater and improved understanding of cellular events in cancer, leading to development of rational treatments; (vi) Greater understanding of genes involved in human development; (vii) Genome analysis of important microbes, and discovery of new antibiotics for their therapy; (viii) Recognition of new drug targets for all diseases, based on sequence analysis of genes and receptors, and faster development of new drugs; (ix) Better understanding of stem cell biology and its therapeutic implications; (x) Devising innovative therapies, e.g., anti- sense or gene-based, for curing disease; (xi) An era of pharmaco-genomics leading to individualized medicine i.e., determining the most appropriate drugs suited for the genetic make up of a particular individual. Epidemiological transition in India India is in epidemiological transition, and not only we have to tackle the burden of infectious diseases, but also the load of non-communicable disorders like birth defects, thalassemias, coronary artery disease, hyper-tension and diabetes mellitus(5). India did not participate in the sequencing of the human genome, but the Government of India through the Department of Biotechnology and Indian Council of Medical Research have recently invested heavily to set up molecular genetic centers in different institutions in India to bring the benefits of these new DNA techniques for our people(6). This presentation will highlight the way the new genetics and genome information has moved from the bench to the bedside, to help better management and treatment of patients. Anatomy of the human genome Doctors are interested in driving a car, rather than knowing how the engine works. I would therefore not describe the anatomy of the human genome in any detail. The human DNA is distributed into 46 chromosomes, half of which come from the mother and half from the father. Therefore the genes located on these chromosomes also occur in pairs. The human gene sequence is but a long line of four letters appearing in print, only some part of which codes for genes. On completing the draft human sequence it was a surprise that the total number of genes is only 30,000 to 35,000, a much smaller number than anti-cipated. Each gene is further subdivided into exons and introns, the exons coding for the active part that is transcribed into RNA and translated into protein. The beta globin gene is the smallest gene in the body comprised of 1200 base pairs, while the Duchenne muscular dystrophy gene is the largest(7). Molecular diagnostics DNA diagnosis of a large number of disorders is currently available. Beta and alpha thalassemias are the commonest genetic disorders in India. We know the mutations in beta globin gene common in different parts (8), and this knowledge along with data on different polymorphisms in locus control region of the gene is utilized for forecasting the prognosis, as well identifying the cases that are likely to respond to hydroxyurea and other manipulations to increase fetal hemoglobin(9). The information on mutations also helps to carry out prenatal diagnosis to reduce the burden of these disorders(10). Deletion screening in Duchenne muscular dystrophy is now the first investigation in place of a biopsy, as about 70% of cases show deletions(11). In those without a deletion muscle biopsy with dystrophin staining becomes mandatory(12). Such information also has therapeutic implications, as the use of oligonucleotides to bypass a single deleted exon, or use of genatmycin in cases of non-functional dystrophin due to a stop codon. This knowledge also helps carrier screening and prenatal diagnosis to reduce the burden of this distressing disease in future generations. Spinal muscle atrophy is the commonest autosomal recessive disorder next to thalassaemia. The molecular test for deletion of exon 7 is the only sure shot method to confirm the diagnosis, as well as to provide prenatal diagnosis in future generations(13). Understanding the molecular biology of the SMN gene has generated the hope of therapy for this dreaded disorder(14). Many other genetic disorders are amenable to molecular diagnosis – hemo-philia, cystic fibrosis, alpha1 antitrypsin deficiency, Wilson’s disease, achondroplasia, Apert syndrome, Prader Willi syndrome, Angelman syndrome, Factor V Leiden, Huntington disease, myotonic dystrophy, spinocerebellar ataxias 1,2,3,6,7 and 12, congenital adrenal hyperplasia and mitochondrial mutations (MELAS, MERRF, LHON, NARP, Leigh’s). We are in the process of establishing the Indian mutations in oculocutaneous albinism, alkaptonuria and a few other diseases(13). Prenatal diagnosis In India the socio-economic burden of disease is very high, as the parents have to cover the cost of treatment themselves, without much help from the government. Therefore, prenatal diagnosis is greatly in demand. No one wants to have an affected child. The advent of molecular diagnostics extended the availability of prenatal diagnosis for many more disorders, thus allowing the affected families to have normal children without fear of delivering an abnormal child. This became possible not only for common disorders like thalassemia, spinal muscular atrophy, Duchenne muscular dystrophy, but for rarer disorders like familial hypercholes-terolemia and congenital adrenal hyperplasia. Asymptomatic diagnosis The power of DNA technology is such that it enables the doctors to detect the abnormal gene in subjects much before they have any symptoms of the disease(15). This is a great boon, for example in Wilson disease as therapy can be started early before the development of serious symptoms so that the individual stays normal. This is however a double-edged sword. For disorders like Huntington disease or spino-cerebellar ataxia which manifest only in adulthood, knowing that you have an abnormal gene much before you have any symptoms engenders a lot of anxiety and mental tension. The right "not to know", therefore, has to be recognized and respected. Functional genomics Identifying the gene and knowing its structure is not enough. One must learn its function, and then only one can devise rational therapy. Thus, after the sequencing era, functional genomics would be the big thing. India can make a major contribution because of its strength in computer softwares, which can be put to good use in the field of bio-informatics to identify new genes and their function(16). Pharmacogenomics Pharmacogenomics will develop in a big way, so that individualized therapies will be developed. It is known that each one of us has a different nucleotide at every 1000 bases. Such changes are called single nucleotide polymorphisms. They occur either in the intergenic region (in between the genes) or in the introns, which do not code for RNA. Such changes are responsible for the individuality of a person, and also influence the way a person handles the administered drugs(17). The study of pharmacogenomics will allow us to use the drug most appropriate for a person thus avoiding side effects, and increasing effectiveness. For example, children who have an arginine at codon 27 in the beta-adrenergic receptor for both alleles respond much better to albuterol than if they are homozygous for glycine(18). DNA micro-arrays to study the function of genes have been of great help in oncology, leading to the discovery of molecular signatures for particular types of cancers, to defining their prognosis, and selection of the appropriate chemotherapy. Microbial genomics A large number of bacteria and viruses have been completely sequenced, including important ones like tuberculosis and H. influenzae(21). This is likely to improve the diagnostic methods and also provide easy and early diagnosis of resistant bacteria. Lot of effort is being expended to discover new drug targets on the genomes of the bacteria. Microbiology is poised for a complete revolution, as most of the infectious diseases would be diagnosed by molecular methods in the coming decade. Gene and gene-based therapy A strong armamentarium of recombinant protein therapies already exists – erythro-poetin, growth hormone, insulin, growth factors, interferon, and hepatitis B vaccine. New recombinant proteins are on the horizon, right here in India. If current research is successful, DNA vaccines would prove more efficacious, and may in the future be administered through plants – bananas, potatoes and tomatoes. Gene therapy has been limited by the non-availability of good and safe vectors, but better vectors are under development. Gene therapy is a reality in a limited way for cancer, and is likely to be successful for other disorders(21). The Future of Genomics The completion of the genome sequence is not the beginning of the end, but is only the end of the beginning(22). The next decade will see the study of the transcriptome representing all of the transcripts or RNA copies of the genes in a cell; proteome, representing all of the proteins in a cell, tissue or individual; and metabolome, representing all of the molecular components of a cell or tissue produced by the proteins(23). We are in for a veritable revolution in the practice of pediatrics – the diagnosis of infections, development of vaccines, new treatments for old bacteria, predictive medicine, and innovative therapies. The field of agriculture would also be revolutionized, and many transgenic plants would be propagated and used to alleviate hunger and malnutrition. A truly amazing future awaits us. What is now required is that more training in genetics be imparted and more genetic centers be opened so that the tremendous benefits of this technology are utilized for the benefit of many patients in India now and in future(24). I. C. Verma, |
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