Lecture 2 - Intro To Systems Biology

LECTURE 2 SEPTEMBER 11, 2024 INTRODUCTION TO SYSTEMS BIOLOGY  Systems Biology The overall objective of the BIOL 1080 course is to consider the concepts of Health, Disease and Aging in the adult human from a “Systems Biology” per...

LECTURE 2 SEPTEMBER 11, 2024 INTRODUCTION TO SYSTEMS BIOLOGY  Systems Biology The overall objective of the BIOL 1080 course is to consider the concepts of Health, Disease and Aging in the adult human from a “Systems Biology” perspective. Systems Biology: “the systematic study of complex interactions in biological systems.” Main goal of this system is to “better understand the entirety of the processes that happen in a biological system.” i.e. the opposite to the usual “reductionist paradigm” where organizational levels tend to be isolated. Reductionist Approach: “something can be best explained by reducing complex phenomena into their most basic parts” 2  Systems Biology SB considers interactions and dynamics – in short, complexity! “Systems biology studies biological systems by perturbing them (biologically, genetically, chemically) and monitoring the gene, protein and informational pathway responses; and ultimately, formulating mathematical models that describe the structure of the system and its response to individual perturbations” Ideker et al 2001. Annual Review of Genomics and Human Genetics 2:343-372, 2001. What makes you, YOU! 3  Systems Biology SB incorporates many levels! from genes to proteins to tissues to organ systems Main purpose is to predict outcomes or responses in a living system. This involves complex mathematical modeling! This is generally referred to as BIOINFORMATICS Includes a new vocabulary... “omics” Genomics: study of an organism’s complete set of DNA Proteomics: study of the set of all proteins produced within a biological unit; typically, this could be an organ, an organ system, or the entire organism Metabolomics: study of metabolites within a given unit; e.g. cell, tissue, organ, organism 4  Reduction vs. Integration “.. Systems biology is about putting together rather than taking apart, integration rather than reduction” (2006, Denis Noble. The music of life: biology beyond the genome – Oxford Press) “The reductionist approach … offers no convincing concepts to understand how system properties emerge” (2007, Science 316:550) Organizational levels tend to be isolated! Isolated models (molecules, Integrated whole-body or organism cells, organs or tissue, etc.): approach: - Exquisite control over - Less control over variables experimental conditions - Viewed as LESS mechanistic i.e., - Can elucidate mechanisms what factor was the most important? - But what does it mean in vivo? - But more REAL WORLD! 5  Reduction vs. Integration Sometimes You Get Different Outcomes EXAMPLE 1 Stimulation of fat oxidation in muscle by the anti-obesity hormone, leptin ISOLATED fat oxidation Data in the lab shows that leptin is good at burning fat! Possible conclusion: Leptin administration will help with Within 30 min... weight loss? time But first, consider that: This isolated test is done in the absence of hundreds of other hormones that could antagonize, or even amplify leptin’s effects Leptin has numerous effects in other tissues, including the brain Overweight individuals become leptin resistant Clinical trials with leptin have NOT been very successful! 6  Reduction vs. Integration Different Outcomes Example 2 What Limits Maximal Oxygen Uptake (VO2 max)? Whole body exercise (cycling, running) – this is the more traditional “integrated” model. Cardiac output is main limiter of VO2 max in this model. Single leg extensions – this “reduction” model can be used to study training effects in the absence of “systemic changes” and to allow for comparisons to the untrained leg in the same person. Muscle mitochondrial content limits VO2 max in this model. 7  A Clinical Example: Type 2 Diabetes and Regulation of Blood Glucose Current Diagnosis is a Reductionist Approach: Fasting blood [glucose] > 6.9 mM OR OGTT result >11.1 mM (@ 2 hrs) Considerations: Time: Only a single time point! Location: A single site! Context: Doesn’t tell you WHY blood glucose is increased! Is the problem chronic or only after large carbohydrate meals? Is the problem at the liver or skeletal muscle? Is the problem sensing glucose and secreting insulin (pancreas)? If we don’t know WHY blood glucose is elevated, is it logical to use a “one drug fits all ”approach? e.g. rosiglitazone, metformin 8  A Nutritional Example: Should You Take Antioxidants or Not? Antioxidants are molecules that protect against damage from reactive oxygen species (ROS) in your body. ROS can cause harm if levels become too high in your body. They are linked to aging and multiple diseases. 9  A Nutritional Example... Should You Take Antioxidants or Not? YES! Reactive oxygen species (ROS) can induce oxidative damage (DNA, proteins, lipids), promoting aging and disease Antioxidants protect the cell from these damaging effects NO! A certain amount of ROS is protective (e.g. leads to apoptosis of damaged cells) ROS are a natural signal involved in adaptation (e.g. adaptation to exercise training) Some studies show that Vitamin C/E supplementation BLOCKS mitochondrial adaptations to exercise training! L 10  A Nutritional Example... Should You Take Antioxidants or Not? 6-8 weeks training, humans and rats Vitamin C dosage Men: 1000 mg/day (recommended dose is ~ 75-100 mg/day) Rats: 500 mg/kg/day (would be ~ 36 g for humans!) Am J Clin Nutr. 2008. 87(1):142-149. 11 A Nutritional Example: Should You Take Antioxidants or Not? Training-induced increase in VO2 max appears blunted by Vitamin C in both humans and rats L Training-improved endurance (only tested in rats) also appears blunted by Vitamin C L Note the small sample size (n=6)! Vitamin C supplementation prevents some of the beneficial cellular adaptations to exercise training L 12 A Nutritional Example: Should You Take Antioxidants or Not? Do You Have Enough Information to Know What to Do? What if I have low levels of ROS? Would supplements be unnecessary or even harmful (overwhelm protective mechanisms of ROS)? What if I have high levels of ROS? And low endogenous antioxidant defenses? Maybe I should take them? What about different tissues/organs? Prostate (lycopenes), eye (lutein) What if you could screen for various markers (genes, proteins, metabolites i.e. “omics”*) to help you decide? * genomics, proteomics, metabolomics 13  Table 1. Application of Reductionism versus Systems-Oriented Perspective to Medicine Ahn AC, Tewari M, Poon C-S, Phillips RS (2006) The Clinical Applications of a Systems Approach. PLoS Med 3(7): e209. doi:10.1371/journal.pmed.0030209 http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.0030209 14 Which of the following is best associated with a systems-oriented approach to medicine? a) Conditions where one or a few components are responsible for the overall behaviour of the system b) Conditions where interactions between components are responsible for the overall behaviour of the system c) Types of diseases tend to be acute and simple diseases, such as a urinary tract infection d) Both B and C e) All of the above 15  TAKE-AWAY POINTS: Biological processes are complex and sometimes difficult to predict! Reductionism examines specific responses in isolated, controlled situations. Integration examines more wide-spread responses in less controlled, but more realistic situations. Systems Biology is an integrated approach to better understand the complexity of biology. Most chronic diseases are also complex, affecting many systems, and are probably best studied using more of a Systems Biology approach. 17