Chris E Cooper

• PhD Biophysics
• Professor (Full) at University of Essex

The clinical utility of hemoglobin-based oxygen carriers (HBOC) is limited by adverse heme oxidative chemistry. A variety of tyrosine residues were inserted on the surface of the γ subunit of recombinant fetal hemoglobin to create novel electron transport pathways. This enhanced the ability of the physiological antioxidant ascorbate to reduce ferry...

Hypercapnia increases cerebral blood flow. The effects on cerebral metabolism remain incompletely understood although studies show an oxidation of cytochrome c oxidase, Complex IV of the mitochondrial respiratory chain. Systems modelling was combined with previously published non-invasive measurements of cerebral tissue oxygenation, cerebral blood...

Hypercapnia increases cerebral blood flow, but the effect on cerebral metabolism in humans remains incompletely understood. Either increased or reduced oxygen consumption has been predicted from Fick models incorporating cerebral oxygen extraction fraction and cerebral blood flow. Hypercapnia also results in oxidation of cytochrome c oxidase, compl...

The purposes of the present investigation were: 1) to explore the utility of Near Infrared Spectroscopy (NIRS) as a measurement tool within triathlon; 2) create a profile of the physiological responses to triathlon. A laboratory based study explored the utility of multi-site NIRS as a measurement tool within triathlon using recreational male triath...

PEGylation of protein sulfhydryl residues is a common method used to create a stable drug conjugate to enhance vascular retention times. We recently created a putative haemoglobin-based oxygen carrier using maleimide-PEG to selectively modify a single engineered cysteine residue in the α subunit (αAla19Cys). However, maleimide-PEG adducts are subje...

The aim of the present study was to examine whether full leg-length compression tights modify physiological and kinematic measures during treadmill running at a competitive race pace in moderately trained runners. Thirteen males and five females completed two 15-minute running tests at a speed corresponding to a recent race time wearing compression...

In order to use a Hemoglobin Based Oxygen Carrier as an oxygen therapeutic or blood substitute, it is necessary to increase the size of the hemoglobin molecule to prevent rapid renal clearance. A common method uses maleimide PEGylation of sulfhydryls created by the reaction of 2-iminothiolane at surface lysines. However, this creates highly heterog...

In order to infuse hemoglobin into the vasculature as an oxygen therapeutic or blood substitute, it is necessary to increase the size of the molecule to enhance vascular retention. This aim can be achieved by PEGylation. However, using non-specific conjugation methods creates heterogenous mixtures and alters protein function. Site-specific PEGylati...

This study examined the effects of Sprint Interval Cycling (SIT) on muscle oxygenation ki-netics and performance during the 30-15 intermittent fitness test (IFT). Twenty-five women hockey players of Olympic standard were randomly selected into an experimental group (EXP) and a control group (CON). The EXP group performed six additional SIT sessions...

Hemoglobin (Hb)-based oxygen carriers (HBOC) are modified extracellular proteins, designed to replace or augment the oxygen-carrying capacity of erythrocytes. However, clinical results have generally been disappointing due to adverse side effects, in part linked to the intrinsic oxidative toxicity of Hb. Previously a redox-active tyrosine residue w...

Heme mediated oxidative toxicity has been linked to adverse side effects in Hemoglobin Based Oxygen Carriers (HBOC), initiated by reactive ferryl (FeIV) iron and globin based free radical species. We recently showed that the addition of a redox active tyrosine residue in the beta subunit (βF41Y) of recombinant hemoglobin had the capability to decre...

Hemoglobin (Hb)-based oxygen carriers (HBOCs) are an investigational replacement for blood transfusions and are known to cause oxidative damage to tissues. To investigate the correlation between their oxygen binding properties and these detrimental effects, we investigated two PEGylated HBOCs endowed with different oxygen binding properties - but o...

Hemoglobin (Hb)-based oxygen carriers (HBOCs) have been engineered to replace or augment the oxygen carrying capacity of erythrocytes. However, clinical results have generally been disappointing, in part due to the intrinsic oxidative toxicity of Hb. The most common HBOC starting material is adult human or bovine Hb. However, it has been suggested...

The development of an underwater near-infrared spectroscopy (uNIRS) device has enabled previously unattainable measurements of peripheral muscle hemodynamics and oxygenation to be taken within the natural aquatic environment. The purposes of this study were (i) to trial the use of uNIRS, in a real world training study, and (ii) to monitor the effec...

The purpose of the study was to compare muscle oxygenation as measured by two portable, wireless near-infrared spectroscopy (NIRS) devices under resting and dynamic conditions. A recently developed low-cost NIRS device (MOXY) was compared against an established PortaMon system that makes use of the spatially resolved spectroscopy algorithm. The inf...

Covalent hemoglobin binding to membranes leads to band 3 (AE1) clustering and the removal of erythrocytes from the circulation; it is also implicated in blood storage lesions. Damaged hemoglobin, with the heme being in a redox and oxygen-binding inactive hemichrome form, has been implicated as the binding species. However, previous studies used str...

Due to the technical nature of speed skating, that is affecting physiological mechanisms such as oxygenation and blood flow, this sport provides a unique setting allowing us to uncover novel mechanistic insights of the physiological response to exercise in elite middle-distance and endurance sports. The present study aimed to examine the influence...

Hemoglobin based oxygen carriers (HBOC) have been engineered to replace or augment the oxygen carrying capacity of erythrocytes. However, clinical results have generally been disappointing due to adverse side effects linked to intrinsic heme-mediated oxidative toxicity and nitric oxide scavenging. Redox-active tyrosine residues can facilitate elect...

The brain responds to hypoxia with an increase in cerebral blood flow (CBF). However, such an increase is generally believed to start only after the oxygen tension decreases to a certain threshold level. Although many mechanisms (different vasodilator and different generation and metabolism mechanisms of the vasodilator) have been proposed at the m...

It has been proposed that introducing tyrosine residues into human hemoglobin (e.g. βPhe41Tyr) may be able to reduce the toxicity of the ferryl heme species in extracellular hemoglobin-based oxygen carriers (HBOC) by facilitating long-range electron transfer from endogenous and exogenous antioxidants. Surface-exposed residues lying close to the sol...

To date, measurements of oxygen status during swim exercise have focused upon systemic aerobic capacity. The development of a portable, waterproof NIRS device makes possible a local measurement of muscle hemodynamics and oxygenation that could provide a novel insight into the physiological changes that occur during swim exercise. The purpose of thi...

Hypoxia-ischaemia (HI) is a major cause of neonatal brain injury, often leading to long-term damage or death. In order to improve understanding and test new treatments, piglets are used as preclinical models for human neonates. We have extended an earlier computational model of piglet cerebral physiology for application to multimodal experimental d...

The reaction of oxyhemoglobin with nitric oxide is known to occur in vivo, with direct medical and pathophysiological relevance. The mechanism has been proposed to involve a transient iron(III)-peroxynitrite intermediate, the formation of which would be rate-limiting and the decay of which would yield iron(III)-aqua/iron(III)-hydroxo hemoglobin. Re...

This study examined the effects of Sprint Interval Cycling (SIT) on muscle oxygenation ki-netics and performance during the 30-15 intermittent fitness test (IFT). Twenty-five women hockey players of Olympic standard were randomly selected into an experimental group (EXP) and a control group (CON). The EXP group performed six additional SIT sessions...

The purpose of this research was to waterproof a near-infrared spectroscopy device (PortaMon, Artinis Medical Systems) to enable NIR measurement during swim exercise. Candidate materials were initially tested for waterproof suitability by comparing light intensity values during phantom-based tissue assessment. Secondary assessment involved repeated...

We re-determined the near infrared (NIR) spectral signatures (650-980nm) of the different cytochrome c oxidase redox centres, in the process separating them into their component species. We confirm that the primary contributor to the oxidase NIR spectrum between 700 and 980nm is cupric CuA, which in the beef heart enzyme has a maximum at 835nm. The...

The nitrite adducts of globins can potentially bind via O- or N- linkage to the heme iron. We have used EPR (electron paramagnetic resonance) and DFT (density functional theory) to explore these binding modes to myoglobin and hemoglobin. We demonstrate that the nitrite adducts of both globins have detectable EPR signals; we provide an explanation f...

In most team sports, intermittent high intensity sprint efforts combined with short recovery periods have been identified as a key factor of physical performance; the ability to repeat these efforts at a sustained level is of great importance. Near-infrared spectroscopy (NIRS) has been proposed as a tool to monitor muscle oxygenation changes during...

The present invention relates to a modified porphyrin-based oxygen-carrying protein, such as haemoglobin, which has been found, in its unmodified state to have a low affinity site of electron transfer and a high affinity electron transfer between a reductant and ferryl haem iron via one or more protein amino acids. The invention provides such prote...

The production of nitric oxide by hemoglobin (Hb) has been proposed to play a major role in the control of blood flow. Because of the allosteric nature of hemoglobin, the nitrite reductase activity is a complex function of oxygen partial pressure PO2. We have previous developed a model to obtain the micro rate constants for nitrite reduction by R s...

Hydrogen sulfide (H2S), a classic cytochrome c oxidase inhibitor, is also an in vitro oxidase substrate and an in vivo candidate hormonal ('gasotransmitter') species affecting sleep and hibernation. H2S, nitric oxide (NO) and carbon monoxide (CO) share some common features. All are low-molecular-mass physiological effectors and also oxidase inhibit...

Portable near-infrared spectroscopy (NIRS) has been shown to be a useful and reliable tool for monitoring muscle oxygenation and blood volume changes during dynamic exercise in elite athletes. The wearable nature of such technology permits the measurement of specific muscles/muscle groups during realistic sport-specific exercise tasks in an outdoor...

Portable near-infrared spectroscopy (NIRS) devices were originally developed for use in exercise and sports science by Britton Chance in the 1990s (the RunMan and microRunman series). However, only recently with the development of more robust, and wireless systems, has the routine use in elite sport become possible. As with the medical use of NIRS,...

The brain's response to hypoxia is to increase cerebral blood flow (CBF). However, the molecular mechanism underpinning this phenomenon is controversial. We have developed a model to simulate brain blood flow and oxygen metabolism called BRAINSIGNALS. This model is primarily designed to assist in the interpretation of multimodal noninvasive clinica...

The production of nitric oxide by the nitrite reductase activity of hemoglobin has been proposed to play a major role in hypoxic vasodilation. The bimolecular reaction rate constant for nitric oxide formation is a complex function of hemoglobin oxygenation stemming from the intrinsic allosteric character of hemoglobin, resulting in an unsymmetrical...

Aim: Hemoglobin (Hb) becomes toxic when released from the erythrocyte. The acute phase protein haptoglobin (Hp) binds avidly to Hb and decreases oxidative damage to Hb itself and to the surrounding proteins and lipids. However, the molecular mechanism underpinning Hp protection is to date unclear. The aim of this study was to use electron paramagn...

The redox state of cerebral mitochondrial cytochrome c oxidase monitored with near-infrared spectroscopy (Δ[oxCCO]) is a signal with strong potential as a non-invasive, bedside biomarker of cerebral metabolic status. We hypothesised that the higher mitochondrial density of brain compared to skin and skull would lead to evidence of brain-specificity...

We have developed a computational model to simulate hypoxia-ischaemia (HI) in the neonatal piglet brain. It has been extended from a previous model by adding the simulation of carotid artery occlusion and including pH changes in the cytoplasm. Here, simulations from the model are compared with near-infrared spectroscopy (NIRS) and phosphorus magnet...

Wearable, wireless near-infrared (NIR) spectrometers were used to compare changes in on-ice short-track skating race simulations over 1,500 m with a 3-min cycle ergometry test at constant power output (400 W). The subjects were six male elite short-track speed skaters. Both protocols elicited a rapid desaturation (∆TSI%) in the muscle during early...

The brain responds to hypoxia with an increase in cerebral blood flow (CBF). Many mechanisms have been proposed for this hypoxic vasodilation, but none has gained universal acceptance. Although there is some disagreement about the shape of the relationship between arterial oxygen partial pressure (PaO2) and CBF, it is generally agreed that CBF does...

Using transcranial near-infrared spectroscopy (NIRS) to measure changes in the redox state of cerebral cytochrome c oxidase (Δ[oxCCO]) during functional activation in healthy adults is hampered by instrumentation and algorithm issues. This study reports the Δ[oxCCO] response measured in such a setting and investigates possible confounders of this m...

Purpose: Previous work identified an asymmetry in tissue desaturation changes in the left and right quadriceps muscles during on-ice skating at maximal speed in males. The effect of changing race distance on the magnitude of desaturation or leg asymmetry is unknown. Methods: Six elite male skaters (age = 23 ± 1.8 yr, height = 1.8 ± 0.1 m, mass =...

Mitochondrial cytochrome c oxidase (CCO) is responsible for >95% of mammalian oxygen consumption, and is key to generation of the electrochemical proton gradient required for the bulk of ATP production. Nitric oxide (NO) is a signalling molecule with roles including the control of blood flow and blood pressure via activation of soluble guanylate cy...

The production of nitric oxide by the nitrite reductase activity of deoxyhemoglobin has been proposed to play a major role in hypoxic vasodilation. A feature of this mechanism is that deoxyhemoglobin sites in the R state of tetrameric hemoglobin favoured at high pO2 have enhanced activity compared to deoxyhemoglobin sites in the T state tetramer fa...

Noninvasive approaches to measuring cerebral circulation and metabolism are crucial to furthering our understanding of brain function. These approaches also have considerable potential for clinical use "at the bedside". However, a highly nontrivial task and precondition if such methods are to be used routinely is the robust physiological interpreta...

In patients with migraine, an abnormally large haemodynamic response to epileptogenic visual stimulation has previously been observed, consistent with the hypothesis of a cortical hyperexcitability. Ophthalmic filters have been used in the treatment of migraine, and they reduce the haemodynamic response. The present study used near-infrared spectro...

Tyrosine residues can act as redox cofactors that provide an electron transfer ("hole-hopping") route that enhances the rate of ferryl heme iron reduction by externally added reductants, for example, ascorbate. Aplysia fasciata myoglobin, having no naturally occurring tyrosines but 15 phenylalanines that can be selectively mutated to tyrosine resid...

The use of a mathematical model of cerebral physiology and metabolism may aid the interpretation of experimentally measured data. In this study, model outputs of tissue oxygen saturation (TOS) and velocity of blood in the middle cerebral artery (Vmca) were compared with experimentally measured signals (TOS using near infrared spectroscopy and Vmca...

We describe a computational model to simulate measurements from near-infrared spectroscopy (NIRS) and magnetic resonance spectroscopy (MRS) in the piglet brain. Piglets are often subjected to anoxic, hypoxic and ischaemic insults, as experimental models for human neonates. The model aims to help interpret measurements and increase understanding of...

To investigate the effects of warm-up intensity on all-out sprint cycling performance, muscle oxygenation and metabolism, 8 trained male cyclists/triathletes undertook a 30-s sprint cycling test preceded by moderate, heavy or severe warm up and 10-min recovery. Muscle oxygenation was measured by near-infrared spectroscopy, with deoxyhaemoglobin ([H...

We report the use of a novel dual-channel hybrid near infrared optical spectrometer for the measurement of changes in oxidized cytochrome c oxidase (oxCCO) concentration and optical scattering in 11 healthy volunteers during functional activation induced by an anagram-solving task. A haemodynamic response consistent with functional activation was s...

The use of a mathematical model of cerebral physiology and metabolism may aid the interpretation of experimentally measured data. In this study, model outputs of tissue oxygen saturation (TOS) and velocity of blood in the middle cerebral artery (Vmca) were compared with experimentally measured signals (TOS using near-infrared spectroscopy and Vmca...

We report the use of a novel dual-channel hybrid near-infrared optical spectrometer for the measurement of changes in oxidized cytochrome c oxidase (oxCCO) concentration and optical scattering in 11 healthy volunteers during functional activation induced by an anagram-solving task. A hemodynamic Changed ‘haemodynamic’ to ‘hemodynamic’ though follow...

In 1996, the Royal Society held a Discussion Meeting entitled 'Near-infrared spectroscopy and imaging of living systems'. In 2010, this topic was revisited in a Theo Murphy Royal Society Scientific Discussion Meeting entitled 'Making light work: illuminating the future of biomedical optics'. The second meeting provided the opportunity for leading r...

A week after our meeting, we received the very sad news that Britton Chance had passed away on 16th November 2010, in Philadelphia, aged 97. Britton was an extraordinary scientist who made an enormous impact in so many areas of biochemistry and biophysics. He was a leading figure in biomedical

Nitrate reductases (NRs) are enzymes that catalyze reduction of nitrate to nitrite using a molybdenum cofactor. In an alternative reaction, plant NRs have also been shown to catalyze reduction of nitrite to nitric oxide, and this appears to be a major source of nitric oxide synthesis in plants, although other pathways have also been shown. Here, de...

We previously reported that high micromolar concentrations of nitric oxide were able to oxidize mitochondrial cytochrome c at physiological pH, producing nitroxyl anion (Sharpe and Cooper, 1998 Biochem. J. 332, 9-19). However, the subsequent re-evaluation of the redox potential of the NO/NO(-) couple suggests that this reaction is thermodynamically...

It has been suggested that, because of the low sitting position in short-track speed skating, muscle blood flow is restricted, leading to decreases in tissue oxygenation. Therefore, wearable wireless-enabled near-infrared spectroscopy (NIRS) technology was used to monitor changes in quadriceps muscle blood volume and oxygenation during a 500-m race...

Resolving for changes in concentration of tissue chromophores in the human adult brain with near-infrared spectroscopy has generally been based on the assumption that optical scattering and pathlength remain constant. We have used a novel hybrid optical spectrometer that combines multi-distance frequency and broadband systems to investigate the cha...

Resolving for changes in concentration of tissue chromophores in the human adult brain with near-infrared spectroscopy has generally been based on the assumption that optical scattering and pathlength remain constant. We have used a novel hybrid optical spectrometer that combines multi-distance frequency and broadband systems to investigate the cha...

The peroxidase-type reactivity of cytochrome c is proposed to play a role in free radical production and/or apoptosis. This study describes cytochrome c catalysis of peroxide consumption by ascorbate. Under conditions where the sixth coordination position at the cytochrome c heme iron becomes more accessible for exogenous ligands (by carboxymethyla...

A new approach to measure muscle oxygen saturation (SmO(2)) using near infrared spectroscopy (NIRS) has been proposed in this paper. This approach exploits the cyclic NIRS signals seen during exercise which are often regarded as "movement artefacts". This new measure, which we term the "cyclic SmO(2)", has the potential to be less affected by the m...

Near infrared spectroscopy (NIRS) can readily report on changes in blood volume and oxygenation. However, it has proved more problematic to measure real-time changes in blood flow and oxygen consumption. Here we report the development of a novel method using NIRS to measure local oxygen consumption in human muscle. The method utilizes the blood vol...

We report a novel methodology that combines NIR multi-distance frequency and broadband spectrometers to quantify brain tissue haemodynamics, oxygenation and metabolism. We show preliminary results in a young healthy adult during a CO2challenge.

In recent years there has been widespread use of near infrared spectroscopy (NIRS) to monitor the brain. The signals of interest include changes in the levels of oxygenated and deoxygenated haemoglobin and tissue oxygen saturation. In addition to oxy- and deoxy-haemoglobin, the Cu(A) centre in cytochrome-c-oxidase (CCO) is a significant NIR absorbe...

Reduction of detergent-solubilized formate-inhibited beef heart cytochrome c oxidase +/- cytochrome c in turnover with ascorbate was followed aerobically. Heme c, heme a and CuA steady states were monitored. Heme a and CuA were in equilibrium with each other, and with cytochrome c when the latter was present. In the formate system there is no aerob...

A new approach to measure muscle oxygen saturation (SmO2) using near infrared spectroscopy (NIRS) has been proposed in this paper. This approach exploits the cyclic NIRS signals seen during exercise which are often regarded as "movement artefacts". This new measure, which we term the "cyclic SmO2", has the potential to be less affected by the myogl...

For resolving absolute concentration of tissue chromophores in the human adult brain with near-infrared spectroscopy it is necessary to calculate the light scattering and absorption, at multiple wavelengths with some depth resolution. To achieve this we propose an instrumentation configuration that combines multi-distance frequency and broadband sp...

In recent years there has been widespread use of near infrared spectroscopy (MRS) to monitor the brain. The signals of interest include changes in the levels of oxygenated and deoxygenated haemoglobin and tissue oxygen saturation. In addition to oxy- and deoxy-haemoglobin, the Cu-A centre in cytochrome-c-oxidase (CCO) is a significant NIR absorber,...

For resolving absolute concentration of tissue chromophores in the human adult brain with near-infrared spectroscopy it is necessary to calculate the light scattering and absorption, at multiple wavelengths with some depth resolution. To achieve this we propose an instrumentation configuration that combines multi-distance frequency and broadband sp...

Adipose content in the region over the vastus lateralis muscle was measured in a young (21.1 +/- 3.1 years old, mean +/- SD) population of males (n = 62) and females (n = 28). Three techniques were used: skinfold thickness, ultrasound and near infrared spectroscopy. All techniques closely correlated with each other and all showed a significantly la...

The steady-state behaviour of isolated mammalian cytochrome c oxidase was examined by increasing the rate of reduction of cytochrome c. Under these conditions the enzyme's 605 (haem a), 655 (haem a3/CuB) and 830 (CuA) nm spectral features behaved as if they were at near equilibrium with cytochrome c (550 nm). This has implications for non-invasive...

Hemoglobin has a range of enzymatic activities that can affect its putative pharmacological role as an extracellular oxygen carrier. In the presence of peroxides, deoxyhemoglobin and methemoglobin can produce free radicals and induce lipid peroxidation. Oxyhemoglobin can oxidize the free radical nitric oxide to nitrate, yet deoxyhemoglobin can prod...

The aerobic respiratory chain of Escherichia coli has two terminal quinol oxidases: cytochrome bo and cytochrome bd. Cytochrome bd was thought to function solely to facilitate micro-aerobic respiration. However, it has recently been shown to be overexpressed under conditions of nitric oxide (NO) stress; we show here that cytochrome bd is crucial fo...

In the visible/NIR (600 – 900 nm) three different redox centres are potentially detectable in vivo in mitochondrial cytochrome c oxidase: haem a (605nm), the binuclear haem a 3/CuB centre (655 nm) and CuA (830 nm). In this paper we report changes in the steady state reduction of these centres following increases in the rate of electron entry into t...

The effect of seizures on brain blood flow and metabolism has been extensively studied. However, few studies have focused on mitochondria. We used near infrared spectroscopy (NIRS) to study hemoglobin and cytochrome oxidase changes during seizures, induced by the GABA antagonist bicuculline, in the adult rat. A broadband spectroscopy system was use...

This study investigates the relationship between changes in brain tissue haemodynamics, oxygenation and oxidised cytochrome-c-oxidase ([oxCCO]) in the adult brain during hyperoxia and hypercapnea. 10 healthy volunteers were studied. We measured the mean blood flow velocity of the right middle cerebral artery (Vmca) with transcranial Doppler (TCD) a...

We construct a model of brain circulation and energy metabolism. The model is designed to explain experimental data and predict the response of the circulation and metabolism to a variety of stimuli, in particular, changes in arterial blood pressure, CO(2) levels, O(2) levels, and functional activation. Significant model outputs are predictions abo...

Supplementary material (0.21 MB PDF)

The four gases, nitric oxide (NO), carbon monoxide (CO), hydrogen sulfide (H(2)S) and hydrogen cyanide (HCN) all readily inhibit oxygen consumption by mitochondrial cytochrome oxidase. This inhibition is responsible for much of their toxicity when they are applied externally to the body. However, recently these gases have all been implicated, to gr...

The lack of blood donations and the threat of infections from blood and blood products have led to extensive research into the development of blood substitutes. The latest generation of hemoglobin based oxygen carriers (HBOC) has been shown to induce side effects like hypertension, vasoconstriction, inflammation and oxidative stress. HBOC are able...