Life after human genome map

THE WORKING draft of the human genome is a kin to man landing on the moon. However, the lunar landing truly saw the culmination of years or prolonged research, careful planning and perfect execution marked by high precision. The effort and success in sequencing the human genome, is quite the contrast, because the journey has just begun for these scientists.

The human genome project (HGP) is yet another example of a successful partnership forged between the private industry and a public funded institution in the United States. Celera Genomics of Rockville, Maryland a private enterprise and the federally funded National Human Genome Research Institute at the Jackson Laboratory, Bar Habor, Maine, took on the daunting task of deciphering the human genome. Employing what has come to be known in scientific parlance as the `shotgun technique', Celera churned out 99% of the sequence while the federal outfit deciphered 85% of the genome and in fact is on schedule to create a detailed map of 99.99% accuracy by year 2003.

The sequence at hand is a composite of but six individuals and the number of genes in a human being is still a toss up, estimated 30,000 and 120,000! Add to it is the genetic diversity in the human race. Given that nearly 95% of the human genome is unimportant, sifting the functional components and eliminating the `junk' is a tedious task. Here, Nature lends a helping hand. A comparison of genomes across a wide array of species helps deciphering the functional genes because genes are conserved in evolution and are remarkably similar across diverse species. The genomes of mouse, fruit fly, zebrafish and other species hitherto consigned to obscure passions of pursuit of a fanatical few now zoom into prominence. Biochemical pathways are fairly, regularly comparable, no matter whether one looks at pathogens or Homo sapiens.

The human genome project also holds the key to a better understanding of diseases and for creating specifically crafted treatments for them. The next critical steps in this much- trumpeted war over diseases would be focus on messenger RNA (mRNA) and proteins.

The study of cellular proteins, the next link in the chain, is known as proteomics. All life is made up of proteins and there are as many 50,000 to 2 million of them in living forms. Beyond identifying every one of these proteins, equally important would be to characterise their shape and structure. Delineation of protein structure is arduous and less than 1% of all known proteins have been characterised entirely. But nearly all the proteins involved in critical pathways are conserved across the species and sifting through piles of data generated from comparative studies helps target the more common, well conserved and repetitive proteins. Targeting complex diseases afflicting the heart, the central nervous system or those leading to cancers is at the root of this mammoth effort. Whereas all the various digitised technologies such as bioinformatics, protemics and DNA chips are critically important and do provide valuable clues to how genes function, it is the analogue mammalian system in mouse that provides the holistic answers.

Employing knockout mice (ones that lack only one particular gene) heralds the next phase in drug development and is well set to make in vivo mammalian studies which takes you closest to the real thing happening.

One of the discoveries from the present study of human genome is the discovery of innumerable single nucleotide polymorphisms (SNPs) which is akin to a long sentence which has one random alphabet changed. That some 30 million SNPs occur in an organism might provide the explanation for predisposition to diseases or to the varied responses to the same drug.

Genes, besides coding for proteins within the cell, are also known to network and have a, yet poorly understood, role in intracellular communications. Signalling pathways wherein cells trigger synthesis of proteins in organs that are spatially separated (such as the secretion of various digestive juices) are other major systems to be elicited before designing more efficacious drugs.

Indeed the future of biology rests on an understanding of how genes act and equally how they interact. Yet, the focus will shift to the proteins that they code and how these proteins interact in a cellular matrix that will carry the day more than genomics per se.

Gurumurti Natarajan

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Section  : Science & Tech
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