Basic Biological BackgroundOrganisms are grouped into different "classes" with a hirachical structure. For example, E. coli is a bacterium belonging to the kingdom of prokaryotes. It is a very popular "model" system to investigaste basic principles of life. Many principles seen at this "simple level" of life apply to many other organisms, including humans, which belong to the eukaryotes. Following, a very short introduction with focus on human molecular biology is given.
About Cells, Genes and Proteins - Recalling some BasicsThe cell is the principle unit of life. It is a chemical system where thousands of reactions and transformations are carried out next to each other to allow its own survival and reproduction. The human body consists of approximately 1014 such cells, but can be subgrouped into organs. The cell itself can be subgrouped into organelles, which reside in the cytoplasm and are separated by membranes. One of these is the nucleus where deoxyribonucleic acid (DNA), the molecule of inheritance, is the major constituent. DNA is a polymer of deoxyribonucleotide units in which the bases adenine (A), cytosine (C), guanine (G) and thymine (T) are linearly aligned. DNA consists of two complementary strands and therefore base pairs (bp) are the principle unit of length. The helical structure of the double strand was solved by Watson and Crick in 1953.
Importantly, DNA encodes for proteins, the work horses of the cell, whereof amino acids are the principle structural unit. Decoding is accomplished by transcribing DNA information into mRNA, which has to maturate (so called introns have to be deleted in an event called splicing), and is exported out of the nucleus before it then can be translated into protein. Oversimplified, one gene codes for one protein, and a triplet of three bases determines the corresponding amino acid in a linear fashion. Twenty different amino acids offer a wide variety of physicochemical properties and only the folded protein can exert its function. Proteins can act as enzymes, catalyzing chemical reaction, e.g. those involved in metabolism providing energy or those replicating or transcribing DNA, as scaffolding proteins giving the cell shape and order or as motor proteins enabling motility of the cell or within the cell, e.g. along scaffolding proteins for transport.
Another important role of proteins is that of signaling. They are required to receive, integrate and distribute signals. There are many levels of regulation. In principle, the amount of a certain protein can be regulated first by the amount of production (here any of the stages from transcription to translation can be influenced) and second by its stability. The activity of the protein can be modified and represents another level of regulation. This very short description of basic biological principles is extended in many good textbooks devoted to the subject (e.g. Stryer 1999, Alberts et al. 1997).
Human Genome as an Example - from Genomics to Proteomics to Systems Biology20 years ago deciphering a piece of 1000 bp of DNA kept a whole laboratory busy for months. Today, high throughput DNA sequencing is becoming a routine, and 1000 bp are only a matter of seconds in modern sequencing centers. So far, global efforts have enabled deciphering the code of more than 30 organisms including the human. In a joint effort Craig Venter (Celera Genomics) and Francis Collins (International Human Genome Consortium), heading a privately and publicly funded effort respectively, reported the human genome to be sequenced to more than 90% in February 2001 (Lander et al. 2001; Venter et al. 2001), with most of the data generated within less than two years (http://www.genome.gov, www.ornl.gov/hgmis).
The human genome consists of ~3 x 109 bp. Neglecting somatic mutations (and somatic recombination) each cell within the human body contains the same genome. Once thought of as containing more than 105 genes, this number lowered to 3 x 104 genes at the beginning of 2001, with the number being slightly corrected again nowadays (~4.5 x 104 (Pennisi 2001)) and the exact number still being unknown. 40% of the genes have so far no ascribed molecular function! 9% are thought of to be involved in signal transduction (Venter et al. 2001). If alternative splicing, secondary modifications like phosphorylation or ubiquitinylation and different complex formations are taken into account, the actual number of components of a cell is well larger, although not all genes are turned on in every cell at any time. This highlights that the sequencing is not the end, but the beginning of understanding the genome and how it is used. The fact that the human and the chimpanzee genome are 98 % identical underlines this impressively (Ebersberger et al. 2002).
Which genes are expressed at any time can be monitored globally by gene chips, and expression profiling has become a widely employed systematic approach to monitor a cells behavior globally under different conditions, e.g. tumor versus normal cell, knock out versus normal cell or different cell types. But as explained above the genome delivers its information through proteins, and as there are many levels of posttranscriptional regulation, measuring amounts of mRNA alone cannot provide a complete understanding. Proteome data are harder to retrieve on a global level, and technology development will be a key point for the advancement of proteomics.
There have been recent systematic approaches to elucidate interaction in yeast (Uetz et al. 2000; Ito et al. 2001) through so called two hybrid screens, and the data was used for a nice comparison in which the authors, for example, find that links between highly connected proteins are systematically suppressed, whereas those between a highly connected and low-connected pairs of proteins are favored (Maslov and Sneppen 2002). As function is achieved through dynamic interaction within a complex network, examination of the presence of a molecule within a certain cell type at a certain time point is not the only important aspect. Topological and dynamic aspects have to be considered. As we have seen so far, although the biological information is growing rapidly, there are still many questions left open, and the dynamic behavior of the constituents within a cell is far from being elucidated. Understanding of those principles will be key in unterstanding biology. Information science is needed to deal with the huge amounts of data, and so systems theory will be needed to understand the complex, dynamical chemical systems involved. Systems Biology is integrating those sciences to promote understanding.
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