The announcement that the human genome sequencing project was entering the final phase was greeted as a landmark in the history of humankind, and compared to the invention of writing and printing and the landing of man on the moon (http://www.sanger.ac.uk/). In fact, nothing so exceptional happened that day, but rather in the decade that preceded. The real revolution in biology and medicine took place when diabetes patients or those suffering from anemia caused by renal deficiency began being treated with insulin or recombinant human erythropoietin, and when substances such as growth factors, whose presumed existence had been shown indirectly, began to be part of the daily therapeutic arsenal.
Anyway, this date should be considered inconsequential. Full knowledge of the structure of the human genome will not, on its own, lead to immediate practical results, since a considerable number of possible interactions between the different proteins and genes will have to be explored before biological activity can be understood based on the relationship of the genome with the environment. The enormous plasticity of the simplest biological systems ensures that this will be no small task in human beings. Nonetheless, even though incomplete, knowledge of the human genome plays an important role in establishing the limits and, with considerable accuracy, the shape of information, so that we can begin to work with a complete picture and not just a bit of it. But the most important consequence is that it makes the planning and the undertaking of the next steps feasible and necessary.
And, what are the next steps? It is not difficult to speculate on the immediate future, because the post-genomic era in fact began some time ago and is already producing results. The study of the expression of the complete genome of the S. cerevisae, examination of the expression of 8,600 human cell genes and 6,800 human neoplasia genes offers us a completely new view of the life of a cell (Science 283:83, 1999; PNAS 97: 3364, 2000; Science 286:531, 1999). Some significant approaches to the post-human-
genome era are shown in the attached table. The most important question of the moment is to try to see how this will affect scientific planning in Brazil. What should our specific concerns and responsibilities be as researchers, and what are those common to all citizens? Should we respond based on the recent success of FAPESP’s initiative in sequencing genomes, beginning with Xylella, which introduced a successful system (decentralized work in a network, objective, simple and well-defined, internal and non-competitive collaboration within the group, supervised by an external steering committee).
The success of the initial work, focusing on a simple genome, permitted an increase of the organisms to be studied or to be considered for study (X. citri, sugar cane, parasites, virus, among other things). Nonetheless, only the Human Cancer Genome Project (HCGP) has been included so far, and indirectly, in the most complex and competitive area of the human genome, in fact a form of post-genomic approach, since it focuses on expressed sequences (derived from mRNA) and not DNA. Undertaking this project made the advantages of this strategy clear; it led, for example, to the identification of almost half a million EST sequences in a year (compared with 760,000 in the National Cancer Institute’s CGAP project in three years) and it allowed the discovery of more than a hundred genes along the published sequence of chromosome 22. The Human Cancer Genome Project should, therefore, serve as a basis for expanding the initiative of researchers in São Paulo regarding the human genome, with the intention of identifying genes and studying coded proteins, analyzing expression in various situations and studying the diversity of the human genome (beginning with the discovery of the single nucleotide polymorphisms in the sequences identified).
A necessary challenge to be overcome now is the transposition of this system and the extension of the project to applied medical fields. Clinical genomics could be defined as the use of information from sequencing DNA and its variability, the discovery of genes or patterns of genetic expression for medical ends. A limited form of this approach would be to set up networks of associates made up of clinical and surgical groups to choose, monitor and treat patients with certain diseases and according to standardized protocols, correlating the results with variations in expressed genes, in order to identify genes that are relevant to diagnosis, prognosis, or therapeutic response. More ambitious forms of project for genetic epidemiology are already being undertaken in Iceland and Britain (Science 287:1184, 2000).
The setting up of the ONSA network and FAPESP’s different genome projects have changed the character of great part of the scientific community in São Paulo, spurring a huge competence leap, in addition to the direct effects of the concrete results and international visibility for the scientists involved. The resources employed, however, can still be considered modest, at around US$ 30 million over three years, and, of this, only US$ 5 million was spent on the single component of the project that focuses man, the Human Cancer Genome Project (along with around US$ 5 million from the Ludwig Institute for Cancer Research).
By way of comparison, Brazil spent in a year (1999) around US$ 120 million on importing coagulation factors, albumin, and immunoglobulins, biological substances required for treating a small group of patients with hemophilia and other blood diseases. To a large degree obtained by processing surplus human plasma, some of these biological agents can be produced by recombinant DNA technology, and this is just an example of the applications that researchers in São Paulo could help solve. The scientific community in the state of São Paulo has shown that it is able to achieve ambitious and competitive goals; it just needs to be organized around projects that have clearly defined limits and proper funding
Approaches in the Post-Human Genome Era
• Discovery of genes, identification of proteins and analysis of expression
• Analysis of expression in different stages of ontogenetic development, specific variations of each tissue and different stage of diseases such as neoplasia
• Identification of the bases of human genetic diversity
• Correlation of genetic variations with susceptibility to “acquired” diseases (such as thrombosis, heart attack, autoimmune disease)
• Organization of clinical and surgical groups for correlation studies
• Application of genetic engineering techniques for the production of biological substances of medical interest
Marco Antonio Zago is a professor of Medical Practice at the Medicine School at Ribeirão Preto, USP, technical-scientific director of the Ribeirão Preto Hematology Center and coordinator of one of the sequencing centers of the Human Cancer Genome ProjectRepublish