When Oxygen-Sensing Genes Go Wrong

When Oxygen-Sensing Genes Go Wrong - Life-saving treatment on one hand, performance-enhancing drug on the other – erythropoietin, also known as EPO, is a classic example of how one substance can be used for both good and bad purposes.

For chronic kidney disease patients suffering from anaemia, the synthetic version produced via recombinant DNA technology is a life-saving hormone that replaces the natural EPO, which is no longer being adequately produced by their failing kidneys.

EPO is a crucial factor in red blood cell production, and red blood cells are vital in transporting oxygen to the cells in our body.

However, it is this very function that also makes it a performance-enhancing drug, especially for endurance sports like cycling.

By taking EPO, athletes increase their red blood cell production, enabling more oxygen to get to their muscles, which boosts their performance.

Within a decade or so of the EPO gene being isolated and synthetic EPO produced, this substance was officially banned by the World Anti-Doping Agency.

The agency has been testing for synthetic EPO usage in athletes since the 2000 Sydney Olympics.

However, advancements in research have resulted in the development of drugs that can stimulate natural EPO production in the body.

And even though the most advanced of these drugs are still in phase III clinical trials and not approved for human consumption outside of these trials, two professional cyclists have already tested positive for one of them and been issued four-year bans.

Interestingly, University of Cambridge Regius Professor of Physic Dr Patrick Maxwell notes that there are some people born with genetic mutations that make them hypersensitive to EPO.

“If you go back to the 1960s, there was a champion cross-country skier who had a mutation in the EPO receptor, which meant that it was a bit switched on, and so he had a haemoglobin that was much higher than yours or mine.

“And he did win Olympic gold medals,” he says.

This skier was Finland’s seven-time Olympic medallist Eero Mäntyranta, who was competitively active from 1960 to 1972. Research on his family showed that several of his relatives also had this mutation.

When genes mutate

Prof Maxwell, who is also Cambridge’s School of Clinical Medicine head, was involved in much of the research that uncovered that all cells can sense oxygen and how they do it.

When Oxygen-Sensing Genes Go Wrong - He says: “Along the way, one of the things that have been interesting is we’ve identified humans with genetic mutations in the pathway that lead to the oxygen-sensing mechanism not quite working normally, either in all cells or just some cells.

“And that actually helped us work out how the sensing works.”

He explains: “So, some people are born with a faulty copy of one of the key genes, and the cells work normally because we all have two copies of every gene and one normal copy is enough for the cell to work.

“But every so often the cell makes a mistake in copying the normal gene. That means you then have none of the normal proteins and that cell behaves as if it is getting no oxygen.

“And that’s enough to mean that those individuals will get kidney cancer in their lifetime.”

While Prof Maxwell says that the cancer is usually the result of a number of genetic errors accumulating over time, it is a reason to be cautious about the new drugs under development.

“That’s another reason why we need long-term studies to understand the condition.”

He and his team have also identified another genetic mutation that results in the body’s cells thinking there is less oxygen than there actually is. “And these people have a few more red blood cells than you or me.”

Interestingly, this particular genetic mutation does not seem to increase the affected person’s chances of getting kidney cancer, although they are at risk of the side effects of thicker blood, like a predisposition to clotting and blood vessel blockage.

He shares that the core oxygen-sensing pathway involves six genes, three of which are particularly important in the production of red blood cells.

“They are active in all cells, but they are critical in the kidney cells for getting the right amount of EPO,” he says.

Prof Maxwell was in town recently at the invitation of Sunway University as part of their collaboration with Cambridge to establish the Sunway Clinical Research Centre as a Regional Site Partner of Cambridge’s School of Clinical Medicine.