BIOL*1080 Systems biology

health

the state of complete physical, mental, and social wellbeing, not just an absence of disease and infirmity

7 characteristics of life

• ability to reproduce

• growth

• can metabolize

• made of cells

• passing of genes to next generation

• maintain homeostasis

• response to stimuli

emergent properties

properties can only be observed when individual components are interacting as a group in a system

genetic homology (humans to chimps and fruit flies)

chimpanzees - 98%

fruit flies - 65%

what coordinates functions in human systems

CCN (control and communication network)

components of CCN 4

• central nervous system (brain and spinal cord)

• peripheral nervous system (somatic, autonomic)

• endocrine system (hormones, endocrine tissues, exocrine glands)

• support and defence system (support, movement, maintenance, repair, adaption, defences (specific and non-specific)

properties of CCN (CARDI)

• always on

• controls and coordinates function of all system and organs

• distributed throughout entire body

• has redundancy (back up)

• information flow via chemical and cell to cell communication

the CCN is the _____ of health

focal point

what does the CCN do

receive internal (eg. nutrients, hormones) and external (stress, infections, social interactions) environment input

processes these signals to determine if health is maintained or drift towards disease

the CCN is the integrator of…

inputs to health, disease, and aging

output to the seven dimension of health

seven dimensions of health (SEE MOPS)

spiritual, physical, occupational, mental, environmental, social, emotional

lifestyle medicine

therapeutic modality that addresses lifestyle-related contributors to non-communicable disease

8 pillars of lifestyle medicine

• healthy eating

• regular exercise

• restorative sleep

• stress management

• positive social connection

• avoidance of substances and behaviour

• hygiene

• positive environmental connection

what represents compromised function/structure of the CCN

disease and aging

what results in disease processes

diminished/abnormal CCN

what results in aging

reduced function int he CCN

examples of disease due to diminished CCN

diabetes - abnormal endocrine and support and defence systems

cancer - support and defence system

depression, ADHD - central nervous system

examples of aging because of reduced CCN

Alzeimer’s - central nervous system

diminished touch sensitivity - peripheral nervous system

impaired wound healing - support and defence system

p4 medicine

personalized, predictive, preventative, participatory

p4 medicine example: nutritional genomics

about 50% of population has GA or AA variant that makes them greater to cardiovascular disease with high caffeine intake

Cochrane reviews

a database of systematic reviews and meta-analyses which summarize and interpret the results of medical research

experimental models for human medical and health research

• in silico

• in vitro and ex vivo

• animal models

• human participants

in silico

computer/mathematical simulation model

in vitro

“in glass”

ex. cell culture in Petri dish

ex vivo

“out of the living”

ex. isolated organs/tissues

main purpose of in vitro and ex vivo

allows for more controlled experimental condiitons

understanding fundamental mechanisms

examples of animal models 6

• C. Elegans

• Drosophila Melanogaster (fruit fly)

• rats

• mice

• swine (piglets)

• primates

Why are C. Elegant (nematode) used as models 5

• easy to study and cheap

• short life cycle

• self-fertilizes

• can be frozen, thawed, and remains viable

• transparent (for cell differentiation)

research examples of C. elegans

embryonic metabolism

use a fluorescent tag to follow digestion of a nutrient, synthesis of proteins, cholesterol

why are Drosophila Melanogaster used as models

life cycle and development are very sensitive to environmental conditions

used to research effects of drugs and alcohol

why are rats used as models

very social and intelligent

used to study lifestyle effects on metabolism (diets, exercise, drugs)

tend to take “more severe approach” than with humans

some genetically modified rats

zucker rats

rats lacking leptin receptors

used to study obesity and diabetes

limitation of using rat models

not good for studying human infant nutrition and metabolism

why are mice used as models 3

easily genetically modified (DNA knockout)

can test important of single protein, though may have compensatory mechanism

used to study lifestyle effects on metabolism (can differ from rats)

OB/OB mouse

mouse lacking ability to produce leptin

can you assume one rodent model = another

no

ex. muscle metabolism can differ (mitochondria adapt less robustly)

takes longer to make a mouse insulin resistant on a high fat diet vs. rats

why are swine used as models 2

best non-primate model for human infant development and metabolism

used to study organ transplants

types of experimental designs

non-clinical studied (non-invervention)

clinical studied (intervention)

clinical study (intervention)

medicinal/lifestyle treatment and/or control stance/placebo

used to predict cause and effect

best standard for medical and healthcare research

RCT, double-blind, placebo-controlled

non-clinical studies

no medicinal/lifestyle treatment given

cannot prove cause and effect, predicts correlation

observational

most common non-clinical study

epidemiological studies (patterns of health and disease)

why are primates used as models

closest genetic homology to humans

cons of using primates

costly

many ethical controversies

they feel more complex emotions

little research in Canada

what research are primates used for

human pathologies (AIDS)

transplantation

drug abuse, toxicology

systems biology

the systematic study of complex interactions in biological systems

main goal of systems biology

to better understand the processes that happen in biological systems

predict outcomes and responses in living system

bioinformatics

biology that involved complex mathematical modelling

levels of systems biology

genes, proteins, tissues, organ systems

genomics

study of organisms’ complete set of DNA

proteomics

study of set of all proteins produced within biological unit

can be organ, organ system

metabolomics

study of metabolites in given unit

in cell tissue organ organism

reductionist approach

isolates models (molecules, cells, organs, or tissue)

control over experimental conditions

explains mechanisms

integration

integrated-whole body/organism approach

less control over variables

less mechanistic

ex. integrative vs reductionist - leptin

leptin, signals fullness to brain to maintain healthy weight

lab data shows leptin is good at burning fat (reductionist)

leptin becomes resistant in obese individuals

ex. integrative vs reductionist - maximal oxygen intake

r - single leg extensions. muscle mitochondrial content is limiter of VO2 (max oxygen intake) max

I - whole body exercise. cardiac output is limiter of VO2 max

ex. integrative vs reductionist - type 2 diabetes diagnosis

is reductionist

takes single blood sample to determine glucose level

doesn’t tell WHY blood glucose is elevated (time, location, context?)

ex. integrative vs reductionist - omega-3 fatty acids

researchers noticed populations eating a lot of fish had lower rates of cardiovascular disease

strong evidence for association between habitual fish consumption and reduced risk of CVD

studies found no significant reduction in major cardiovascular event or mortality when 1g/day omega 3 fatty acid

I - fish

r - fish oil supplementation

good sources of omega 3 fatty acids

fish, nuts, avocado

why is fish integrative

consists other vitamin D, high quality protein, selenium

eating whole fish replaces other protein sources

balance of omega-3:omega-6 is also important

hierarchy of evidence

more relevance to clinical setting

randomized controlled trial: controlled intervention; should be blinded

cohort and case control studies: no intervention

where info begins; in vitro, ex vivo, animal models

humans in clinical trials are _______

volunteers

trials for new drugs (vaccine)

1. preclinical - animal studies before humans

2. phase I clinical - Is it safe

3. phase II clinical - Is it effective

4. phase III clinical - how does it compare to available

5. after approval - assessing long-term use, benefits, and risks

what factors must be considered for optimal decision in evidence based medicine outcome?

patient values, research evidence, clinical data

types of medical approaches (5)

• population based medicine

• evolutionary medicine

• integrative medicine

• one health

• enhancement medicine

population based medicine

• best suited for general population

• seeks to understand and address various factors influencing health/disease

• less personalized

• ex. mass vaccination programs

evolutionary medicine

• application of modern evolutionary theory to understand health and disease

• ex. should we mimic early diets?

integrative medicine

• treats person as whole not just disease symptoms

• emphasizes the therapeutic relationship between practitioner and patient to make use of all appropriate therapies

one health

• promote, improve, and defend the health and wellbeing of all species

enhancement medicine

• medical treatment that intends to improve performance

• ex. botox, nootropics

uses of AI in health research

• multi-omics integration - uncovering new biomarkers

• natural language processing: extracting clinical notes and supporting systemic review

• population and public health: Model disease outbreaks

uses of AI in healthcare practice

• medical imaging and diagnosis

• lifestyle medicine

• medical charting

risks of AI in health research and practice

• environmental impact

• validity and accuracy

• bias and fairness

• privacy and data governance

conclusion about ai

should not have final authority

dimensions of time

trajectory, rhythm, homeostatic, information flow

trajectory

growth and development over years and decades

rhythm

maintenance and repair over days, weeks, and months

homeostasis

regulation of steady state over hours, minutes, seconds

information flow

action potentials and enzymatic reactions over milliseconds and microseconds

lifespan vs health span

how long do I have to live vs. How long do I have to live healthy and independently?

average life span

81 years

average lifespan

72 years old

maximizing health span is…

a goal in most individuals and societies

maximizing lifespan

various attitudes and practices around the world

many moral, ethical, religious implications

aging risk factors (9)

weight, exercise, stress, sleep, education level, blood total cholesterol, blood pressure, smoking, age of parents/grandparents

biomarkers

indicators of biological state of the organism that tracks aging and disease

examples of biomarkers

height

muscle mass

height as biomarker

sharp increase during infancy and childhood

constant until slow decrease after 40 years old

muscle mass as biomarker (male/female reasoning)

generally decrease with age after 40 years old (~1%)

males associated with decrease in testosterone, IGF1, and inactivity

females associated with inactivity

resistance training can help prevent

requirements of biomarker

reflect healthy function or disease processing

predict risk of disease development

what causes shortening height

kyphosis (curving of spine) due to osteoporosis

disk degeneration/compression

chronobiology

the study of timescales and cycles in biology

biological rhythms and examples

ultradian (less than 24 hours) - ex. appetite

circadian (24 hours) - ex. sleep

infradian (more than 24 hours) - ex. menstrual cycle

what are circadian rhythms controlled by

master clock (the brain)

peripheral clocks

what peripheral clocks do

control gene expression, regulation of enzyme actives, neural function, hormone secretion

guided by master clock

what do circadian rhythms coordinate

sleep, nutrient supply, activity patterns with metabolic patters

consequences of disruption of circadian rhythms (in experimental animals) 5

elevated inflammatory cytokines

gastrointestinal function

obesity

metabolic

premature aging

what is critical to maintaining circadian rhythms

lightness and darkness

when is wound healing and vaccinations most effective

the morning

central clock region of brain name

suprachiasmatic nucleus (SCN)

cluster of cells on hypothalamus