SYSTEMS BIOLOGY: A SYSTEMS APPROACH TO UNDERSTANDING THE COMPLEXITY OF BIOLOGY
The Scientists base their research on a principle hypothesis that complex systems can be understood by seeking out its most fundamental constituents. In other words, the complex problems are resolved by dividing them into smaller, simpler and more tractable units. Hence, physicists search for the basic particles and forces; chemists seek to understand chemical bonds; and biologists explore DNA sequences and molecular structures focusing on a particular gene or a protein in their efforts to understand organisms. This approach of “divide and conquer” is termed reductionism (Williams, 1997; Ahn et al, 2006a).
The Biologists Reductionism approach is a science of convenience and complacency. Complacency, however, does not imply correctness. This is best illustrated by John Godfrey Saxe’s poem “The Blind Men and the Elephant”. The poem is based on a story originating from India. The story is about the six blind men who want to know what an Elephant is like. Each blind man describes the Elephant to something different (side=wall; tusk=spear; trunk=snake; knee=tree; ear=fan; tail=rope,) because each one assumes the whole elephant is like the part he touched (Wikisource). In a similar way, the Reductionist biologists investigate individual molecules to understand the complex life processes. Further they extrapolate dogmas from their observations and claim that is the true account of the complex process.
In the last 50 years, the reductionist approach of analyzing individual constituents of biological systems has been successful in revealing the chemical basis of numerous living processes. It has had a profound influence and still impacts on the biological and biomedical research of today. However, due to this level of success, the holders of the reductionist point of view assume that the reductionism, by itself, is sufficient and they can be likened to a parent generation who want their children to walk the same path of success as they did. The reductionist view fails to notice that their approach does not account for the big picture of complexity and robustness of life and similarly the parents seem to be unaware that the world has changed and nothing is the same (Katagiri, 2003).
The reductionsist thinking of biology has encompassed clinical medicine to an extent where the clinicians focus on individual parts to explain the whole. They focus on the disease rather than the state of the person contributing to the disease. They emphasize homeostasis and restore it back by correcting the deviations. They look for one risk factor-one disease because of their inability to work with multiple factor and comprehend their collective influences. They treat each disease individually assuming minimal effects on the treatment of other or additive response of the individual treatment (Ahn et al, 2006a).
One of the proponents of reductionism – Francis Crick. The co discoverer of structure of double helix model of DNA molecule the great physicist turned molecular biologist turned neuroscientist Francis Crick wrote a book Of Molecules and Men. He wrote “The ultimate aim of the modern movement in biology is in fact to explain all biology in terms of physics and chemistry.” This serves as a creed for the congregation of reductionist community, who try to explain the complex life processes based on the physicochemical properties of the individual components. Some neuroscientists belonging to the reductionist community go to the extreme and view consciousness and mental state as chemical reactions that occur in the brain (Gottschling, 2005). They seem to have oversimplified the equation of man and molecules in order to understand the working of brain.
“Men are made up of Molecules
Molecules do not mean Men
Men are more than Molecules”
The complex biological activity is not due to specific individual molecules. To understand the nature of life, an organism cannot be treated similar to machine, a mere collection of components. All living organisms have a unique ability to self damage themselves and self repair any damage to themselves due to ordinary wear and tear. There is no machine replicating this level of complexity. The best and the most sophisticated ones that the humans have built undergo a self test to a very small extent and warn their operators of the faulty components. When the computers fail to carry out the instructions, they communicate to us their failure. They cannot self repair. They are dependent on external agencies for repair and replacements of components (Bowden and Cardenas, 2005).
An organism is a complex system with dynamic relationship and interactions between the components leading to a behavioral system. In order to have a better understanding of the system wide behavior, three factors need to be considered: (1) context – the inclusion of all components involved in a process. (2) time- to consider the changing characteristics of each component; and (3) space- to account for the topographic relationships between and among components (Ahn et al, 2006b). This is comparable to a soccer team. A particular player as an individual irrespective of his strength and skill may not impact the game. All the eleven players or may be ten in certain situations should communicate, adapt to the situation and boost each other to play as a team and emerge as the victorious.
Systems biology is an in-depth investigation of individual biological components at a systems level to understand how a process, a cell, a group of cells, or an organism works as a whole. This will help in understanding the interrelationship of the different components of a process, how they interact, influence and regulate each together. This would be possible by developing theoretical system models that will help us to understand the observation of experiments and design multi-scale experiments that can provide data to confirm or refute the previous model and lead to creation of new models (Ahn et al, 2006a; Sorger, 2005). Systems biologist need to work just like a soccer coach. To start with the coach has a game plan for his team to work on and then based on the team performance makes substitution during the game. Then for the next game, based on the detailed analysis of the team’s performance, he may make minor changes or may come up with a new strategy and different combinations of players.
Systems biology of modeling and multi-scale experiments is a call for the key striker molecular biologist to come together with the other players the chemist, physicist, computational scientist, mathematician and statistician and work as a team to score and unravel the unique complexity of biological systems. The decoding of the human genome, the high-throughput functional genomic tools microarrays DNA array, RNA expression profiling, nanotechnologies and bioinformatics software would provide the data for the biologist to stimulate the complexity of biological networks and systems. These stimulations will help us to speculate the reactions of the systems to a small extent, although we may not be able to spot each and every interaction that takes place (Van Regenmortel, 2004).
The systems approach with its focus on interactions and interrelationship of the components explains the behavior of the system. In chronic diseases such as diabetes, coronary artery disease the equation is non-linear with multiple factors. The multiple factors lead to complex interactions and thus the conditions keep evolving. Therefore the systems approach is appropriate to investigate the chronic conditions. Although not very often we have certain conditions where the reductionism is helpful and systems approach is not. The acute and simple diseases is a pure “penalty shoot-outs” the perfect one – one. The acute condition is such that a particular interaction influences the behaviour of the system. The two approaches are complementary to each other. Thus the approach has to be custom oriented to the needs of the situation (Ahn et al, 2006b).
Edward de Bono (De Bono, 1994) writes about the thinking approaches. The traditional western thinking is based on search and discovery by going deeper into the core of subject. It is rock logic, and uses set rules and definitions. It splits the problem and sets up the dichotomies and contradiction. It uses adversarial arguments and refutations to explore a subject. This system was fashioned by the Greek Gang of Three (Socrates, Plato and Aristotle). It is supposed to be complete comprehensive and perfect. It may have worked then but it has failed in rapidly changing world. It is not flexible and hence cannot deal with the changes. The system is inadequate and complacent. Bono does not merely criticize, but suggest an alternative approach of ‘parallel’ thinking. Parallel thinking uses the flow of ‘water logic’ and accepts the possibilities without judgments. It takes into account both the sides of contradictions and look to design a way forward. Parallel thinking is cooperative parallel thinking
The Traditional and Parallel thinking of the above represent the reductionism and systems biology respectively. The reductionism had failed to decipher the biological complexity. It has also failed in drug development and vaccines design (Van Regenmortel, 2004). The failure is because of the limitations of the reductionism to account for the interrelations and complex interactions of the different components of the biological systems. This has led to the rise of the system approach. Once the systems biologists recognizes the necessity of a systems perspective. Incorporating the systems approach into biological and biomedical research is challenging. These are technical problems such as working with multiple nonlinear variable, generating quantitative information of complex interactions and accounting for uncertainties due to lack of measurements and observation. These challenges are difficult but not impossible to overcome. The biologist along with the physicist, chemist, mathematician, computational scientist and statistician need to work as a team. They need to put together their resources and skills to have system-level understanding of human health and disease at the organism and community level. Thus, the systems biology approach has great potential for the advancement of biomedical research (Ahn et al, 2006b).
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