Cartography in the New Millennium—the Mapping of the Human Genome

In February of this year, initial maps (there are two) of the human genome were simultaneously published in the journals Science and Nature. This technological feat, which comes within 50 years of Watson and Crick's description of the structure of DNA, is a milestone in human achievement, and will have a profound effect on our understanding and treatment of a variety of diseases, including cancer. Some surprising statistics emerge from the extraordinary amount of information now available, even though the project remains incomplete—only about 25% of the genome is in "finished" form, i.e. there are no gaps in the sequence. Very little of the genome, which is estimated at 3.2 million base pairs, actually codes for protein (less than 2%), while present estimates of the number of genes suggest that there are only approximately 30,000 (32,000 and 39,000 from the two versions of the genome)—far fewer than previously thought. Since this is barely twice the number in the nematode worm, Caenorhabditis elegans (19,099), and only three times that of the fruit fly, Drosophila melanogaster (13,601), it would seem that species diversity is accomplished more by the way in which genes work together in molecular pathways within cells, and by relatively small differences in the specific sequences of genes, than by the acquisition of new genes. In this respect, perhaps we ought to be thinking in terms of the functional properties of protein domains rather than in terms of whole genes, for it is ultimately the pattern of functional interactions of gene products, i.e., proteins, that creates different cell types, different arrangements of cells, and different organisms. This is also relevant to cancer, since the joining of one gene with another through the mediation of a chromosomal translocation frequently produces a fusion protein comprised of parts of two different proteins, while the inappropriate expression (or lack of it) of relatively small subsets of proteins, due to a variety of changes that lead to altered expression of genes, can clearly wreak havoc with the functional properties of cells. In both of these respects, it would seem that genetic processes that lead to cancer are closely related to those involved in the evolution of species.

Another remarkable finding is that approximately 45% of the human genome arises from parasitic DNA elements of one type or another, mostly inserted via RNA reverse transcription—indicating that our concepts of vertical evolution have to be rather drastically modified to take into consideration lateral contributions from other organisms. Transgenic organisms clearly occur naturally, and are not the invention of molecular biologists. This phenomenon, which enriches the vertical process of genetic variation within a species, is paralleled at the psychosocial level by the essential role of other living organisms in the development of the human ethos, and by cross-cultural fertilization in the evolution of peoples, religions, and languages.

What will be the influence of this giant step forward on human health? There can be no doubt that it will be extraordinary, although at this point in history, we should not expect sudden dramatic changes. Already approximately 1,000 genes associated with human diseases have been identified, and doubtless, all genetic associations will be ultimately described. In the case of cancer, we can now perceive that the identification of all potentially neoplastic changes in the genome is simply a matter of time. Similarly, understanding the functional differences induced by these changes, or indeed, those created by single nucleotide polymorphisms (snps) that can induce, for example, individual variation in the metabolism of carcinogens or of drugs, is all eminently within our grasp. Indeed, given that the bulk of the sequencing of the human genome was completed in just 15 months, we can safely predict that technology will improve sufficiently rapidly that it will not be long before the genomes of individual persons, or multiple cells from a specific cancer, will be able to be mapped in a matter of hours. Massive computing power and statistical methods, also yet to be developed, will doubtless lead to ultra-rapid methods of manipulating these huge quantities of information and extracting for the patient and /or physician information relevant to the prevention or (probably an increasingly minor role for the health care service provider of the future) the treatment of disease. Prediction of disease (and cancer) risk will be honed to a high degree of accuracy, although potentially marked variations created by the less readily measured interactions with the environment will still need to be taken into consideration. Treatment, which, in the future, will be precisely targeted to the genetic abnormalities, or, more likely, their consequences at the protein level, will also be adjustable to take into consideration individual handling of drugs, and cancer will be curable by therapy no more toxic than is present treatment of disease caused by micro-organisms (the advent of small molecular weight drugs, such as the BCR-ABL tyrosine kinase inhibitor, STI571 is evidence enough for this). It is to be expected that drug combinations will prove necessary to avoid resistance to specific agents through mutation or the use of alternative pathways. The precise cocktail of drugs required, however, will be individualized on the basis of the particular mix of genetic abnormalities in each tumor—this will be much more important than the type of tumor, although it is probable that particular sets of molecular abnormalities, or their manifestations as gene expression patterns (signatures), will lead to considerably more precise classifications of cancer.

There is much that must be learned before these capabilities become commonplace, such as understanding how minor differences in sequence (e.g.,snps) translate into significant functional differences, how protein structure is consequent upon amino acid sequence and how protein structure is modulated by interactions with other proteins. We shall also need to be able to reduce the vast physico-chemical intracellular milieu, comprised of multiple, simultaneously functioning and interdigitating biochemical pathways, to patterns comprehensible to the human mind. Much of this milieu, or proteome, as the pattern of expressed proteins has been called, will be related to the basic processes necessary to the survival (and death) of the cell, whilst others confer upon the cell its particular characteristics, thereby permitting it to play its preordained role in the organism as a whole. And just as a map of the world provides only the crudest of foundations on which to build a true understanding of the geophysical features of our planet, and in turn, of the myriad of interdependent life forms that it supports, so the map of the human genome provides just a beginning to what really matters —the understanding of all aspects of protein structure, function and interactions in cells (a discipline that has been referred to as proteomics)—for this is the means by which the information encoded in the genome becomes manifested as a living organism. A greater challenge, perhaps, than mapping the human genome, but one which, we can now surmise, is not beyond the power of human ingenuity to meet. There will surely be additional surprises along the way, and hosts of bioethical questions raised as we learn to manipulate the genomes (or proteomes) of not only other creatures, but of ourselves —for good or ill. All human knowledge can be used wisely i.e., to the long-term benefit of all, or unwisely, i.e, to the short-term benefit of a few. We can only hope that the powers of Darwinian "natural" selection, subject, henceforth, to increasing adaptation via Lamarckian acquisition of inheritable characteristics, will have been enough to ensure that the wisdom of human beings will eventually be the equal of their technical prowess, for otherwise, nature's introspective gaze will have probed unprotected into the Medusa's¹ eyes, and we shall, eventually, have contributed to nothing more than the fossil record! — IM