Talking toxic gases with Chris Cooper

Toxic gases actually play an important role in the everyday functioning of our bodies. An Essex professor hopes to exactly what role they – and oxygen – play

Our cells make small quantities of nitric oxide, hydrogen sulphide and carbon monoxide all the time, and the body makes use of these chemicals to control blood flow and blood pressure, and help the immune system fight against disease. How the body manages to make use of the molecules without falling foul of their toxicity is a puzzling question – one a professor from the University of Essex hopes to answer.

Professor Chris Cooper from the Department of Biological Sciences has received a £208,395 grant from the Leverhulme Trust to investigate the role of the toxic gases in detail, paying attention to their role with each other and with oxygen.

 Your work involves looking nitric oxide, hydrogen sulphide and carbon monoxide – aren’t these gases toxic?

Most chemicals are toxic in high enough doses. However, these three are especially bad as they are highly potent, colourless and in the case of carbon monoxide (CO) and nitric oxide (NO) odourless. At least with hydrogen sulphide (H2S) the smell of rotten eggs is a bit of a give away and there is some chance of escape!

We have known about these effects for over 100 years. Despite this tragedies still happen. Recent examples include the children in a Corfu hotel killed by carbon monoxide from a faulty heating system and the hydrogen sulphide released from the dumping of industrial waste in the Ivory Coast (the infamous 2006 Trafigura incident). Due to their availability in most households CO and H2S inhalation are common means of committing suicide; more sinisterly CO was the first gas used by the Nazis for mass executions before it was replaced by cyanide.

The gases all share a common means of toxicity. They interfere with the oxygen we need to provide useful energy in the cell. They do this by binding tightly to the blood protein haemoglobin that transports oxygen and the cellular protein cytochrome oxidase that consumes it.

These gases play a role in the human body – what do they do?

The best-studied of the three gasses is nitric oxide. It controls blood pressure and blood flow. An increase in NO signals an increase in blood flow and a drop in pressure, a decrease in NO decreases flow and increases pressure. Blood volume is also affected; for example Viagra works by enhancing the NO signalling pathway and increasing blood volume. NO gas has other roles in the body, for example being involved in memory in the brain. Even its toxicity can be useful: white blood cells synthesise NO to kill invading bacteria.

H2S has been suggested to play a similar role to NO in controlling blood flow, although via a different molecular mechanism. CO reactions are more diverse and seem to work via modulating other signalling pathways.

What then of the toxicity? This is not all bad news; at lower doses the toxic chemistry that occurs at the oxygen consuming enzyme cytochrome oxidase has been proposed to play a signalling role. For nitric oxide enzyme inhibition can trigger free radical production and activate signalling pathways. For hydrogen sulphide it has been suggested that the inhibition of oxygen consumption could trigger a protective metabolic “hibernation” in mice and humans similar to that seen in true hibernating species. The smell of rotten eggs (or flatulence) may seem a strange thing to send you to sleep, but that it what some scientists suggest.

You’ve just been awarded a Leverhulme Trust grant – what will you be doing with it?

I have just appointed two talented researchers – one a biochemist and the other a physical chemist. Our aim is to combine biochemistry and mathematical modelling to explore how these gases inhibit oxygen consumption and – in particular – how they interact with each other. We want to know whether inhibiting oxygen consumption is part of how they work or is it a side-effect that the body always tries to limit. Ultimately we hope to create a mathematical model of brain blood flow and energy metabolism that will incorporate all these effects.

[caption id="attachment_23495" align="alignright" width="150" caption="Chris Cooper"][/caption]

What does your research involve and what do you hope to find?

We will be using purified enzymes and whole cells to understand how the gases interact with cytochrome oxidase. We are going to start with H2S. It has a rich chemistry and we really don’t know which reactions are important. We will use a combination of optical spectroscopy, electron paramagnetic resonance and gas detecting electrodes to evaluate mechanistic hypotheses. These will then be incorporated into a mathematical model.