BIOLOGY in its broadest sense addresses the nature of various molecules, small and macro, which make up the cellular constituents, their structure and function to maintain the integrity, survival, growth, reproduction and differentiation of a cell. Several disciplines like biochemistry, cell biology, genetics and microbiology deal with different facets of both plant and animal cells. Over the last five decades we have seen a phenomenal growth in our knowledge about various biological phenomena. It is generally believed that we will experience a much higher level of understanding of the biological systems in the next decade. The current excitement in biology is driven substantially by the completion of several genome projects, including those related to humans.
In the last decade, a new discipline has emerged in modern biology which is termed as genomics. Genomics in its simplistic definition deals with the sequence content and information present within the DNA which in turn influences various processes of a cell. The emergence of this new discipline can be traced to the Human Genome Project undertaken by an international collaborative effort between both public funded and private enterprise. We have just witnessed the completion of sequencing of the human genome of approximately 3.3 billion base pairs. During the course of this mega project several technologies have been developed which are spin-offs of this enterprise. These are now available for biological and medical scientists to address several fundamental questions pertaining to life processes, development and differentiation and disease processes.
The mapping of the human genome was not the only focus of the human genome project: at its outset the value of sequencing genomes of model organisms was also recognized. Some of these organisms have been particularly amenable to genetic analysis. In part, the sequencing of smaller genomes was considered as a forerunner for large-scale sequencing. At present genomes of about 150 organisms have already been sequenced, including the genomes of several microorganisms related to human disease.
The list of prokaryotic organisms whose genomes have been sequenced reveals different priorities. In some cases, the driving force was to understand evolutionary relationships between different organisms, as in the case of archeal genomes and, in the case of mycoplasma genitialium, to understand what constitutes a minimal genome. For many organisms, however, the primary motivation for genome sequencing was their medical relevance, particularly in the development of more sensitive diagnostic tools and new targets for therapeutics and vaccines.
Given the importance of the plant kingdom, the genome of a simple plant, arabidopsis, has now been sequenced and the sequencing of the rice genome too is almost complete. In several forums questions have been asked why India has not embarked on a complete sequencing of any of the genomes, while a developing country like Brazil has sequenced the genomes of several model organisms. Many members of the biology research community in India feel that since such an exercise is extremely expensive and not hypothesis based, it would affect the funding of smaller intellect based projects. Others, however, argue that for the sake of national pride, India should carry out the full sequencing of the genome of any organism of potential application. Further, we missed a great opportunity to show the world that Indian scientists have the necessary skills and expertise in biology at the highest level. On a happier note, India is a partner in the global network in the rice genome sequencing project. Indian scientists have successfully completed sequencing the long arm of chromosome 11 of the rice genome.
Once the sequence of the human and other genomes is known, what difference will it make? Certainly there will be a great boost to basic research as we grapple with the fundamental biological questions of how our genome is interpreted to specify a particularly function of a cell, tissue, organism and the human individual. The differentiation and establishment of cellular diversity in both uni- and multicellular organisms is indicated by a well-orchestrated and coordinated differential expression of several genes. Differential gene expression in response to specific stimuli leads to differentiation of pluripotent stem cells into different cellular lineages that give rise to different tissue types and organs. Often, an aberration in expression/processing of a gene or a set of genes leads to abnormal development and disease processes.
Newer methodologies such as gene micro array analysis involving DNA chips (that contain thousands of sequence verified cDNA or oligo-nucleotides) offer a tremendous opportunity to undertake global gene expression profiling. Conceptually, the technique is relatively simple and depends on the already available methods conveniently used for nucleic acid hybridization. However, the new technology demands a very high resolution analysis of several thousand spots on a single microscopic slide. Fortunately, the development of software for computers and statistical analysis has helped increase the utility and power of these new technologies. Several laboratories in India have already started using this technology to address important questions in biology, including pathogenesis of some of infectious diseases and cancer. Globally, several advances are being made towards identifying key set of genes associated with a biological phenomenon and certain multigenic disorders like cancer. It is worth noting that scientists have now identified a group of 10 genes that are commonly associated with tumor metastasis.
The completion of the human genome sequence is more a starting point rather than a finish line. One immediate question is what this DNA sequence would mean when the entire science of genetics is predicated on variation. In other words, given the vast diversity of human genomes on the planet, how does one begin to use a whole genome sequence to identify important traits like disease susceptibility?
To address the sequence variation in human population, the Wellcome Trust of UK has started an SNP Consortium and the goal of this consortium is to identify 300,000 single base differences between genomes from different human populations. While most of these differences may not cause disease, the theory is that a sufficiently dense SNP map can provide useful markers for mapping candidate disease genes and studying gene linkages. Such a study entails genotyping a large number of unrelated people with complex of diseases like asthma, diabetes, hypertension and comparing the genotypes to those of healthy controls. It is hoped that ultimately one could identify all of the SNP variations between disease-prone and disease-resistant genomes, providing a map of likely disease-causing loci. There is, however, considerable concern whether large sums of money should be spent on this effort because the utility of such a database and a strong association between the SNP haplotype and the disease phenotype is still not apparent. Nevertheless, some studies have been initiated in India on the SNP mapping of the genes involved in drug metabolism, DNA repair, asthma and diabetes.
Although the DNA sequence arrangement in the genome defines the blueprint of a cell, it is the proteins that are the final actors of the life processes. They function as enzymes, structural proteins, receptors and so on. It is increasingly clear that the number of proteins in a human cell may exceed the total number of genes, some 30,000, by at least two fold because of the phenomenon of alternate splicing. The diversity of proteins is further magnified by post-translational modification such as phosphorylation, acetylation, methylation and so on. Scientists have now begun to address the cellular functions with respect to total protein profile of a cell and this area is called as proteomics. Whereas the human genome sequence is fairly unidimensional and finite, the proteome is multidimensional and constantly changing in response to various environment factors, giving rise to nearly infinite numbers of possible entities.
Similar to the human genome project, a human proteome project has been initiated with particular reference to plasma proteome and liver proteome. Several academic institutions and industries in India have already integrated this new proteomics technology in their research efforts to address issues related to development and differentiation, plant biology, infectious diseases and cancer. Substantial progress is being made in these directions. The technology itself has evolved over the years due to the integration of two-dimensional polyacrylamide gel electrophoresis and mass spectrometry. One limitation of the proteomics technology is that only a subset of total proteome complement can be analyzed in a single experiment due to the limitations of the resolving power of the two dimensional gel electrophoresis. There is continuous effort in evolving newer approaches to take care of this problem.
The functional diversity of proteins is also influenced by its three-dimensional structure. Research on structure-function relationship of proteins has been, and continues to be, a major focus of research in India. One school of thought believes that the next step in modern biological revolution in the post-genomic era is the combined structural and functional genomic approach that will greatly contribute to our understanding of gene function. There is enough institutional expertise and strength in India to solve three-dimensional structure of proteins. Several scientists have made significant contributions in the area of structural biology and a group of Indian scientists are also a part of an international consortium for mycobacterium tuberculosis structural genomics. The availability of genomic sequence of several organisms has also enabled several biochemists and cell biologists to clone, express and study the biochemical function of any given gene. It is expected that for the next decade biochemists will be busy deciphering the function of many unknown genes and may discover new biochemical pathways in many organisms.
Even as the genomic sequence information of several organisms is being elucidated, some people believe that we may be seeing the end of the genomics era. Others argue that it is not that ‘genomics’ has come and gone but that we are at the beginning of a new phase of biology research. The question now being asked in biosciences research is what lies beyond genomics, proteomics and metabolomics. For many biologists, the answer is systems biology, the integrated quantitative study of life’s cellular processes in time and space. Whereas biological science was a mix of descriptive studies and hypothesis testing, systems biology stresses the value of integrating data to suggest models and generate hypotheses to help unravel biological mechanisms and enhance predictive skills.
Systems biology approaches are making inroads into a range of different academic and research programmes. For example, yeast geneticists are using such strategies to uncover the interactive biochemical pathway diagrams of cellular responses to food sources. In microbiology, systems approaches are being employed to uncover mechanisms of antibiotic resistance. Developmental biologists have started applying systems analyses to understand how patterns of gene expression programme the body of early embryos in organisms such as fruit flies and sea urchins through the orderly production of transcription factors. Several biotechnology companies are also using a systems biology approach to pinpoint predictive bio-markers of diseases to identify potential toxicities of promising drug molecules in their early stages of development.
Systems biology is also helping to understand complex pathologies like cancer, cardiovascular disease and autoimmunity. Many researchers around the world have started addressing the question of how cells interpret extracellular and intracellular signals in a context dependent manner. A landmark paper was published in 2001 in Science entitled ‘Integrated genomic and proteomic analyses of a systematically perturbed metabolic network.’ By integrating data from mRNA studies, quantitative measures of specific proteins and assessment of protein-protein, the authors showed that such an integrated approach gives a much richer picture of an organism than individual approaches. Personally, I believe that the systems biology approach gives enormous scope for understanding many biomedical problems. Such studies have not yet been initiated in India and it is high time that efforts are made in this direction.
While the effort to connect genomics and proteomics, and now metabolomics, is clearly on the rise, some important ‘omics’ remain unexplored. In future, there should be progress in areas such as protein-sugar, protein-drug, and protein-hormone interactions. In addition, now that wiring-diagrams (output of systems biology) of various sorts are being constructed for different species, scientists are likely to start comparing systems between species. It is possible that new disciplines to study how the wiring diagram differs between species or changes over time within a species may emerge in response to stress or insults or physiological stimulus. This new area of ‘Network Biology’ is still in its infancy.
The wiring diagram of cellular signalling is analogous to the inner workings of a supercomputer or complex electronic equipment like the systems that keep a passenger plane in the air. It is generally agreed that signalling mechanisms is one such important process that needs redundant mechanisms. It is like the four engines of a 747-jet; if one fails, other engines take over. As with the electronic circuitry of the plane, biology has also evolved positive and negative signals (feedback systems). All taken together form the wiring diagram. Eliminating a single component in this circuit can have unpredictable results. Similarly, biologists are also knocking out one gene at a time to find out a gene function in the biological context. Several approaches have been employed for knockout studies, the latest being the small interfering RNA technology. This approach permits scientists to study gene function in a much shorter time scale. This emerging technology is already yielding valuable information and many scientists in India are employing this approach in their research efforts.
Another area of biological research which has recently generated tremendous excitement is ‘stem cell research’. Stem cells have two important characteristics that distinguish them from other types of cells. First, they are unspecialized cells that renew themselves for several generations through cell division. Second, they can be induced to become specialized cells such as heart muscle or pancreas under certain physiological or experimental conditions. There are two types of stem cells derived from animals and humans, namely, adult stem cells and embryonic stem cells. The adult stem cell is an undifferentiated cell found in a differentiated tissue that can renew itself and differentiate to yield all the specialized cell types of the tissue from which it originated. Embryonic stem cells, on the other hand, are primitive undifferentiated cells from the embryo that have the potential to become a wide variety of specialized cell types.
Many biomedical scientists believe that stem cells can become the basis for treating diseases like Parkinson’s disease, diabetes and heart disease. Considerable effort and research is being put on hematopoietic stem cells, rebuilding of the nervous system with stem cells, repair of damaged heart with stem cells and genetically modified stem cells in experimental gene therapies. Although it was initially perceived as science fiction, some recent success stories provide hope that we may soon understand how to manipulate the stem cells to generate specific cell types making stem-cell based therapies a reality. Efforts at stem cell research, particularly with respect to hematopoietic stem cells, stem cells of the eye and muscle are now underway in India.
The present decade of the new millennium is witnessing an incredible volume of information generated by genomics and proteomics research. The problem of handling this volume of information will not be solved by technology alone. Some visionary people in the biology community feel that a new generation of researchers, who can incorporate information from diverse areas of science into their thought and intellectual process, needs to be trained. In this context, it is worth looking at the present structure of science education in the country and the world. Basic science courses, including biology, chemistry and physics, are often taught without reference to context and acknowledgement that the students are taking other courses. Modern day biologists know their own field very well, but often cannot do basic chemistry or statistics. Consequently, instead of creating a profession of self-sufficient individuals, the typical course of study creates biologists who are dependent on others to get their work done.
The future of biology lies in integrating the knowledge of classical biologists, modern day genomics and bioinformatics with the language and skills of physical sciences, chemical sciences, engineering mechanics and mathematics. It would be worthwhile if a group of scientists from these diverse areas devise a curriculum that can be taught at the undergraduate level so that we have a new generation of biologists who can ask very different and challenging questions. This is already happening at some of the universities in the USA and UK. The Indian educational policy-makers should seriously think of this new biology so that we do not fall behind our counterparts in the West.
