The double-edged sword called oxygen

By Ananya Sen

If you were to enter a time machine and go back to about 3.8 billion years ago, what would you find? Volcanoes spewing carbon dioxide, hydrogen, and methane into the atmosphere, some water, and no oxygen, which means that you would be dead in about six minutes. So how did humans, who are completely dependent on oxygen, come to exist?

Before oxygen, microbes were the only organisms present 3.8 billion years ago, making a living using hydrogen and carbon dioxide to generate methane. This process still occurs in ruminant animals like cows, in the soil, and even in your gut. The microbes also brought in iron, which was abundantly available in the environment; many proteins depend on iron to carry out a diverse array of cellular processes. As a result, cells had pools of iron in them, which was associated with their DNA and proteins.

The trouble began 2.7 billion years ago when a group of bacteria learned to carry out photosynthesis: a process that uses sunlight, carbon dioxide, and water to generate sugars and oxygen. Since oxygen is a reactive chemical, it reacted with environmental iron and other minerals and therefore the levels of oxygen in the atmosphere remained low for a long time.

A billion years later, due to the abundance of photosynthetic bacteria, the amount of oxygen released was far greater than the amount of oxygen lost through reactions with iron and other minerals in the environment. The result: the atmosphere accumulated 21% oxygen, which is the level on Earth today. This change resulted in microorganisms developing new ways to respire. Prior to the oxygenation event, respiration was anoxic. Aerobic respiration is about 16 times more efficient and as a result, microorganisms began to favor aerobic respiration whenever possible.

However, oxygen can react with cellular components to generate dangerous chemicals that are collectively known as reactive oxygen species. One such chemical is hydrogen peroxide, a common chemical found in pharmacies. The reason why hydrogen peroxide is used to clean wounds is because it kills bacteria. Even our body’s defense systems spray invading bacteria with hydrogen peroxide to prevent infection. But why is hydrogen peroxide so dangerous? Because it can react unfavorably with iron sequestered by the cell.

Cells accumulate large pools of iron within them, which associate with DNA and proteins. However, hydrogen peroxide can react with iron to produce hydroxyl radicals, which are extremely reactive and can damage any molecule that they encounter. Think about it: vast pools of iron reacting with hydrogen peroxide to form radicals that can attack DNA and proteins and damage them. It’s a bad situation. In fact, human cells, which have inherited the iron-centric way of life from ancient bacteria, are faced with the same dilemma.

Despite the damage oxygen can inflict inside cells, life persists. How? Cells deal with oxidative stress in two ways: by getting rid of the stress and repairing the damage caused by stress. There are dedicated enzymes that reduce the concentrations of H₂O₂ and other reactive chemicals to innocuous levels. Cells also have proteins that sequester iron thereby preventing the reaction of iron with H₂O₂. And lastly, cells have pathways that are committed to repair damage to DNA and protein.

Understanding oxidative stress, the damage it can cause, and the repair pathways in cells is important because the knowledge can be harnessed for medical purposes. In fact, oxidative stress is already used in cancer treatment in the form of gamma radiation, which is highly energetic and can convert water to hydroxyl radicals thereby starting a chain of destructive effects. Oxygen therapy is also used to combat gas gangrene which is caused by the bacterium Clostridium. The treatment involves the exposure of the bacteria to higher concentrations of oxygen, which increases the concentration of reactive oxygen species and kills the bacteria.

On the flip side, there are several bacteria that are resistant to oxidative killing. Typically, white blood cells in the body engulf invading bacteria and subject them to a stream of hydrogen peroxide. Although this system is sufficient to kill the majority of the bacteria, others such as Salmonella and Mycobacterium tuberculosis can still survive inside the macrophages and cause infections. Therefore, understanding the survival mechanisms of these bacteria will help scientists design methods to undermine bacterial defenses and treat the disease they cause.

Oxidative stress is unique because unlike other stressors which have been present since the beginning of life, life evolved in the absence of oxygen. Although life has adapted to oxidative stress over the last millions of years, life’s fundamental pathways have yet to find a way to embrace oxidative stress. Thus, life contains several vulnerabilities that were irrelevant before oxygen, making oxidative stress a convenient therapeutic tool.

Ananya Sen is currently a graduate student in Microbiology at the University of Illinois at Urbana-Champaign. When she’s not studying oxidative stress, she is busy pursuing her passion for scientific writing. Currently she contributes articles to ASM, ScienceSeeker, and her own blog where she discusses the history of various scientific processes.