Scientists across the disciplines are discovering how oxygen created from
water is pivotal for the evolution of life on earth and how it affects every
aspect of health, disease and development Dr.
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Oxygen from water pivotal for life on earth
It was the tiny blue-green bacteria (cyanobacteria) that invented the production
of oxygen from water and started the great transformation of the earth’s atmosphere
to one suitable for aerobic metabolism and the evolution of complex life-forms
some 2.5 billions years ago..
Photosynthesis as we know it today is responsible not only for
the vital task of taking CO2 out of the atmosphere, but also for
replenishing the atmosphere and the oceans with oxygen that’s essential to
sustain all aerobic life.
The creation of the photosynthetic apparatus capable of splitting
water into oxygen, protons, and electrons, was the pivotal innovation in the
evolution of life on Earth. It gave access to water, a new, unlimited source
of electrons and protons for photosynthesis , thereby greatly expanding
the thermodynamic range of energy available to life. Before that, some bacteria
carried out a form of photosynthesis that does not produce oxygen and depends
on the limited availability of chemical substances that can act as electron
The primitive photosynthetic pigment, bacteriochlorophyll a (BChl-a),
found in green non-sulphur bacteria, when excited by sunlight, has a standard
electrochemical potential of 0.55 V, which is sufficient for using ferrous
iron, carbon and sulphur substrates as electron donors. To use water as electron-donor,
and hence to produce oxygen, requires the creation of the chlorophyll-a in
cyanobacteria and green plants that can be boosted to a higher electrochemical
potential of 0.82 V, thereby giving life access to a higher energy level and
a practically unlimited energy source. This event literally changed the face
of the earth. The accumulation of O2 in the atmosphere led to aerobic
respiration, a much more efficient transformation of energy that generates
18 times more molecules of ATP (adenosine triphosphate) from one sugar molecule
than anaerobic respiration. ATP is the universal intermediate for energy transduction
in living organisms, and is therefore a convenient measure of useful energy.
Aerobic metabolism, in turn, enabled the evolution of complex, multicellular,
energy-efficient eukaryotic organisms, as Lauren Koch and Steven Britton at
the University of Michigan Ann Arbor in the United States argue in a comprehensive
review published in the Journal of Physiology .
To appreciate the momentous importance of getting oxygen from
water, one has to realise that life is energized by nothing more than the
intricately orchestrated flows of electrons and protons carrying negative
and positive electricity respectively. In the process, life creates itself
and transforms the entire earth  (see The Rainbow and the Worm, The Physics
of Organisms, ISIS publication).
Oxygen and the evolution of complex life forms
Life on earth is generally believed to have originated 3.9 billion years
ago, though some scientists have recently put it back as far as 4.4 billions
years ago . The atmosphere was devoid of oxygen, and hence the primordial
organisms were solely dependent on getting electrons from organic compounds
like sugar or inorganic molecules such as hydrogen, sulphide/sulphur, ammonia,
metal/metal ions. Anaerobic respiration cannot make much energy available
to support many activities. Consequently, no multicellular complex organisms
are exclusively anaerobic.
Bacteria capable of harvesting light energy in a primitive photosynthetic
process that does not produce O2 appeared about 3.3 billions years
ago. Oxygen-producing photosynthesis only became established around 2.5 billion
years ago. That initiated the Great Oxidation Event to build up O2
in the atmosphere to 2 percent by 2 billions year ago. The O2 level
remained static for the next billion years when aerobic respiration evolved
and small multicellular organisms became widespread. Between 1.0 and 0.5 billion
years ago, O2 rose sharply to its current level of 20 percent.
This increase is widely believed to have fuelled the ‘Cambrian explosion’,
the rapid evolution of all major animal phyla on earth between 540 and 490
million years ago . Oxygen level then took a steep dive to below 15 percent
before rising sharply to 35 percent 300 million years ago, coincident with
the evolution of large woody land plants with very active photosynthesis .
This period saw the emergence of gigantic insects, as the high atmospheric
O2 concentration lifted the constraint on its availability to tissues
and cells supplied through the insect’s tracheal system . The subsequent
drop in O2 concentration to more or less the present 20 percent
~260 to 234 million years ago is believed to be due to a substantial reduction
in lowland forests and swamps.
A rough correlation is found between increasing oxygen levels
and the rise in the number of different cell types estimated from the protein
sequence data using molecular clock methods  (see Development
and Evolution Revisited, ISIS scientific preprint).. Organisms with two
to three cell types appeared shortly after the initial increase in atmospheric
O2 to 2 percent 2 billions years ago, with further increases occurring
only when O2 started to rise again at 1 billion years ago up to
120 cell types by 0.5 billion years ago when oxygen levels reached 20 percent..
Oxygen is stable, abundant, and fit for life
It is of interest that life is created out of the 85 stable elements; and
7 of the most abundant 10 elements in the universe - hydrogen, helium, oxygen,
carbon, neon, nitrogen, magnesium, silicon, sulphur and iron – are represented
in organisms. So, it is very probable that life anywhere else in the universe
would also be similar to that on earth.
Oxygen is the third most abundant element and has special features that make
it most fit for life. First, the molecules of life are carbon-based, and among
the elements, only nine are more electronegative than carbon and therefore able
to serve as an acceptor of electrons from carbon-based substrates. Of the nine
– selenium, sulphur, iodine, krypton, bromine, nitrogen, chlorine, oxygen, fluorine
– oxygen ranks second only to fluorine in electronegativity, and the other elements
are either a solid, highly reactive, less abundant, or substantially less electronegative.
Thus, reduction of oxygen (burning, transferring electron to oxygen) provides
close to the largest possible transfer of energy for each electron. Another
advantage of oxygen is that it exists typically as a stable ‘triplet’ molecule
consisting of two atoms (O2)  (see The
Body Does Burn Water, SiS 43), which is a freely diffusible gas,
and hence available to all life forms, in the air, on land and in water. Furthermore,
O2 gas is much more easily transported to tissues and cells inside
Oxygen in action past and present
Large evolutionary events are associated with oxygen in the past (see above).
But the evidence is also all around us today .
For example, the trend for animals to be larger at higher latitudes
– polar gigantism - .is best correlated with oxygen. A measurement of 1 853
bottom-dwelling amphipod crustaceans from 12 sites worldwide that included
polar, tropical, marine and freshwater environments revealed a strong correlation
between maximum body length and oxygen content (r2 = 0.98, p<0.0001).
In the lab, a reduction of O2 level by 10 percent decreases body
mass of fruit flies, while an increase O2 level of 40 percent increases
body mass. The atmospheric oxygen burst due to land plants that boosted O2
level in the earth’s atmosphere to 35 percent 300 million years ago and its
subsequent decline to present levels was indeed accompanied by a dramatic
rise and fall in the size of insects.
The fossil record shows that vertebrates started to come on land
about 415 million years ago. Thereafter, the record disappeared for the interval
360-345 million years ago. This 15 million years lull in the fossil record
of vertebrates’ colonization of land, known as Romer’s Gap, remained a complete
mystery until a research team tested the hypothesis that environmental factors
might be responsible. They looked at the ranges of terrestrial arthropods
over the same time period, and found a pattern similar to that of vertebrates;
that is, few new groups evolved for both vertebrates and arthropods during
Romer’s Gap. They suggested that it coincided with, and is explained by the
low atmospheric O2 at the time, less than 15 percent at its lowest
Current global warming is particularly challenging for fish because warming
of the oceans results in less dissolved oxygen at the same time that warm temperatures
pushes up metabolic rate. A study of eel pouts from the North and Baltic Seas
revealed that thermally limited oxygen delivery closely matches environmental
temperatures, and there is a threshold beyond which growth and abundance decrease.
Consequently, warming seas will be the first process to cause extinction or
relocation of organisms to coolers water.
Oxygen makes more energy available and at greater efficiency; at the same
time, it increases the complexity of metabolic networks.
The core metabolic network connects major chemical species (metabolites)
that are transformed by biochemical reactions involved in energy transduction
and mobilisation. It is a very complicated branching network that offers infinite
possibilities for channelling and diverting metabolites to different ends
for maximum effect .
The connectivity of the network of 43 different organisms in
all three domains of life from bacteria to higher organisms was investigated
using the tools of graph theory and statistical mechanics . The analysis
revealed that the metabolites are not randomly connected. Instead the number
of connections per node (metabolite) approximates a power law, P(c)
where c is the number of connections, and P(c) is the
probability of finding a node with c connections. In other words, most
metabolites have one or a few connections, and the number of nodes with many
connections drops off rapidly. Significantly, the most highly connected metabolites
were those associated directly with energy transfer, with water at the top
of the list!
This ‘scale-free’ or fractal network has been found to describe biological
structures and living processes in general [13, 14] (Biology’s
Theory of Everything, SiS 21; The
Heartbeat of Health, SiS 35). It also applies to the World Wide Web,
Internet, and social networks .
A direct investigation on how oxygen availability changed the
architecture of metabolic networks was carried out by ‘seeding’ with a pre-specified
set of metabolites that were allowed to react according to known enzymatic
reaction rules. Once all possible reactions have been carried out, the products
then join the seed metabolites, potentially allowing new reactions to occur.
This process was reiterated until no new products were generated . The
analysis separated four discrete groups of networks of increasing complexity,
with transitions between groups contingent on the presence of the key metabolites:
NAD+, S-adenosyl methionine, coenzyme A, ATP O2, CO2,
NH3, pyruvate or 2-oxoglutarate. The most complex group IV reactions
were associated almost exclusively with the presence of O2, and
had as many as 1 000 reactions more than those of the largest networks achieved
Oxygen in health and disease
Clinical studies reveal a strong statistical association between low aerobic
capacity and death from all causes. In other words, failures of oxygen and
energy metabolism underlie all complex diseases.
In one study, researchers followed 6 213 men for 6.2 years, who
were referred for treadmill exercise testing for clinical reasons. The subjects
were classified into two groups: 3 679 had an abnormal exercise-test result
and/or a history of cardiovascular disease, and 2 534 had a normal exercise-test
result and no history of cardiovascular disease. In both groups, the peak
exercise capacity was a stronger predictor of an increased risk of death compared
with established risk factors such as hypertension, smoking, diabetes, or
the development of arrhythmias during exercise. In all subgroups, the risk
of death from any cause in subjects whose exercise capacity was less than
5 MET (metabolic equivalents) was roughly double those of subjects whose exercise
capacity was more than 8 MET. Each 1 MET increase in aerobic exercise capacity
was associated with a 12 percent increase in survival.
Numerous studies also linked declines in aerobic capacity and
mitochondrial function with type 2 diabetes, cardiac arrhythmias, inflammatory
response, longevity and aging. Physical exercise and aerobic capacity are
associated with reduced cancer risk. Intriguingly, cancer cells are characterized
by a reversion to anaerobic respiration or glycolysis.
Since about 20 years ago, Koch and Britton have tried to create
an animal model that reflects the polygenic nature of a complex disease such
as type 2 diabetes or hypertension. They have come to reject every known
approach including chemical and physical manoeuvres to mimic diabetes, single
or multiple gene knockout models, and mutagenesis. So in 1996 they embarked
on large-scale selective breeding to develop strains of rats that contrast
for intrinsic aerobic treadmill running capacity using a founder population
of 96 breeding pairs . After 21 generations of selection, the low-capacity
runners (LCR) and high capacity runners (HCR) differed by 461 percent in aerobic
The LCR scored higher as young adults on cardiovascular risks
and features of the metabolic syndrome of diabetes, including higher blood
pressure, insulin, random and fasting glucose levels, free fatty acids, visceral
adiposity and triglycerides. The HCR in contrast, measured higher for health
factors such as maximum oxygen uptake, heart function, endothelial nitric
oxide formation, economy of oxygen use and levels of transcription factors
and oxidative enzymes. When exposed to high fat diet, LCR rats gained more
weight and fat mass, and became more insulin resistant. Remarkably, the same
metabolic variables remained unaltered in HCR rats shifted to the high fat
Reactive oxygen species in health and disease
While oxygen has been incorporated into aerobic metabolic processes and became
essential for life, it also produced reactive by-products that damage the
molecules required for life. Consequently, organisms have evolved mechanisms
to protect themselves from oxidative damage and to repair the damage caused
Reactive oxygen species (ROS) refers to a variety of molecules
and free radicals derived from molecular oxygen . They are unavoidable
by-products of aerobic respiration and various other catabolic and anabolic
processes. The respiratory chain produces superoxide that can be converted
to peroxide by superoxide dismutases. Enzymes that produce ROS as by-products
include fatty acyl-CoA oxidase, xanthine oxidase, cytochrome p450 systems,
cyclooxygenases and lipoxygenases. ROS are directly produced from oxygen by
NADPH oxidases, a major family of enzymes first detected during phgocytosis
in special white blood cells, an engulfing process whereby invading microbes
are destroyed; but are now known to be broadly distributed in many tissues,
and increasingly implicated in signal transduction processes and intercommunication
. Specific trans-membrane proteins, aquaporins, initially described as
water channels present in all cells, facilitate the ROS hydrogen peroxide
to diffuse across cell membranes.
Cells have many ways to respond against ROS using enzymatic and non-enzymatic
antioxidants. Common non-enzymatic antioxidants are glutathione (GSH) and thioredoxin.
Glutathione synthesis is catalyzed by the sequential action of g-glutamylcysteins
synthetase and GSH synthetase. GSH is oxidized to GSSG, and the reduce form
can be regenerated by GSH reductase. The balance between GSH and GSSG determines
the redox (reduction-oxidation)/energetic state within the cell. Thioredoxins
(Trx) as well as glutaredoxins (Grx) are small proteins containing an active
site with a redox-active disulfide, and are involved in maintaining a reduced
intracellular redox state in mammalian cells by the reduction of protein thiol
Antioxidant enzymes act in concert to remove various ROS produced.
Superoxide dismutases scavenge the superoxide radical, converting it into
hydrogen peroxide and oxygen. Catalase and the peroxidases convert hydrogen
peroxide into water and oxygen. GSH and Trx are also specific substrates for
a group of peroxidases. The glutathione peroxidases are a group of selenoproteins
that catalyze the reduction of peroxides generated by ROS at the expense of
GSH. Four have been identified in mammals. The Trx-dependent peroxidases are
known as peroxiredoxins and six have been identified in mammals.
An oxidative stress is generated when a cell accumulates an excessive
concentration of ROS beyond what the antioxidant defence can cope with. As
a passive effect ROS can be detrimental to cells due to oxidative damage to
lipids, proteins and DNA. Among the products are lipid hydroperoxides, carbonylated
proteins and DNA with oxidized bases.
While ROS defence is well-established, it is now also generally
accepted that ROS are signalling molecules that transduce messages from the
extracellular milieu to cells to generate a specific response. ROS
have defined functions through modifications of a great diversity of molecules
participating in almost every signalling pathway in the organism. In some
cases redox regulation is indirect through interaction with Trx, for example.
Proteins undergo redox modifications mainly at cysteine (Cys)
residues although other amino acids can be oxidized, such as Tyr, Trp, His.
Proteins subject to ROS modification include kinases and phosphatases that
are themselves key regulators of cellular functions through chemical modifications
of yet other proteins.
Transcription factors that regulate transcription of DNA, likewise, are subject
to ROS regulation. ROS modifications can activate or inactivate the target
ROS is involved in signalling pathways of growth factors and
cell proliferation, and many studies suggest that they may function as classical
second messenger in that the specific response depends on the cell type, the
intracellular compartment where the ROS is produced, the specific ROS and
dose. For example, low and high hydrogen peroxide concentrations produce a
contrasting effect on cells that is dependent on the apoptosis protein p-53;
low doses cause anti-oxidant mediated survival, whereas high doses promote
pro-oxidant mediated cell death.
ROS is now implicated in all aspects of development, from germ
cell formation to morphogenesis, formation of blood vessels and cell migration,
reviving interest in the century-old hypothesis that metabolic gradients guided
early development, and other mysteries of morphogenesis.
Finally, ROS produced by the immune system as defence against
invading microbes, and the extraordinary ability of antibodies and other proteins
to produce powerful bacteriocidal ROS are described in another article of
this series .