Systems Pharmacology
of this process). Administration of a single drug that modulated a specific target changed the con- centration of the diagnostic marker back to a nor- mal range value, reverting the individual’s patho- biological state to healthy status. However, with the advent of systems biology and a new paradigm driven by precision medicine, a greater under- standing of human complexity emerged, concomi- tant with a re-evaluation of the ‘one drug-one tar- get’ paradigm17.
Human complexity and variability In the past, our understanding and appreciation of human complexity and variability at the cellular, individual and population level has constantly been constrained by lack of adequate analytical, bioinformatic and knowledge management tech- nologies. In addition our comprehension of the dynamic nature of human metabolism and physiol- ogy as a function of time was also extremely limit- ed. Furthermore, diagnosis, prognosis and treat- ment decisions had been driven by a reductionist approach, which led to the development of rela- tively simple physiological models, as well as a rudimentary and incomplete understanding of complex biological processes occurring in individ- uals. This has all resulted in a limited ability to make unambiguous and decisive decisions about optimal therapeutic drug treatments for individual patients17. It is salutary to consider the dynamic complexity
and variability of an individual human patient17,18. For example, at the cellular level a single human cell is made up of ~100 trillion water molecules, ~20 billion proteins, ~850 billion fat molecules, ~5 tril- lion sugars and amino acids, ~1.5 trillion inorganic moieties, ~50 million RNA molecules and 2 meters of DNA within 23 pairs of chromosomes. We esti- mate, based on the energy requirements of individ- ual cells in the form of adenosine triphosphate (ATP) turnover, there are ~860 billion chemical reactions/interactions performed per day in a single cell! At the individual level, a single human being consists of ~37.2 trillion cells, made up of 210 dif- ferent cell types, and 78 organs/organ systems. In addition, each one of us hosts ~100-300 trillion microbes, composed of ~10,000 different species that constitute 1-3% of our body weight and con- tain an estimated 8 million protein-coding genes. These micro-organisms play an intimate and inter- woven role in the health and pathobiology of the human host. The molecular machinery of the human body comprises ~19,000 coding genes, ~20,000 gene-coded proteins and 250,000-1 mil- lion splice variants and post-translationally modi-
Drug Discovery World Winter 2018/19
fied proteins, more than 100 million antibodies and ~40,000 metabolites. The combined length of DNA in an individual is calculated at approximately 2 x 1013 meters, which is the equivalent of 70 round trips between the earth and the sun. We estimate also that the total number of chemical reactions/ interactions occurring in a single individual is ~3.2 x 1025 per day! This exceedingly large number is actually greater than the number of grains of sand estimated to be present on the entire planet, which has been calculated at 7.5 x 1018 grains18. A further layer of complexity is that an individ-
ual human is obviously not a closed system. On a daily basis each one of us requires inputs as well as outputs. For example, we consume on average ~1.27kg/day of food and drink (if you are follow- ing current healthy living advice) ~6-8 litres/day of fluid. It is also thought-provoking to consider that more than 25,000 bioactive food and beverage components have been identified. At any one time in the consumption of a normal meal, an individu- al may consume several thousand individual bioac- tive chemicals. In addition we plaster on to our bodies ~100-500 cosmetic ingredients on a daily basis. In terms of output, we lose six litres of fluid/day via urination, which contains ~3,000 active chemical constituents. We also remove on average ~350-500g of solid waste products through defecation on a daily basis and up to six litres of sweat depending on physical exertion. All of this activity is mediated by a transport system consisting of ~100,000 kilometers of arteries, veins and capillaries moving approximately five litres of blood and lymph fluid throughout the body. It is interesting to put all this into context and consider that a modern miracle of technology, the beloved Boeing 747 aircraft, has only six million parts and a mere 285km of wiring or tubing. Is it reasonable to wonder aloud why we struggle with accurate prognosis, diagnosis, and treatment or indeed as to why we actually function at all18? We have previously discussed that it is possible
to quantify human complexity17, but in the case of human variability we are confounded by the range and subtlety of these differences. Such traits can be transitory or permanent and influenced in complex ways by both genetic and/or environmen- tal factors. Sources of human variability include gene mutation (germ-line and somatic), allelic dif- ferences, genetic drift, social and cultural influ- ences and nutrition. Common human variations include obvious visible differences such as gender, age and physical appearance. These differences are determined through poorly-understood molecular processes. Such processes are modulated by a wide
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