Survival of the least unwell

15 February 2017
Posted by Alexandra Ashcroft.

In 1859 Charles Darwin published “On the origin of species”, arguably one of the most influential academic books ever written. Dry and with lengthy prose, I wouldn’t recommend it for bedtime consumption. Yet it is not undeserving of the accolade: the theory of natural selection has impacted nearly every field of biological sciences. Environments select for individuals that are the strongest and the fittest. These individuals succeed in reproducing; their genes are inherited and make up the next generation's gene pool, and the process is repeated. Over time, across generations, change slowly accumulates in biological populations and species adapt to their environments. Science has moved on a lot in 150 years. Our understanding of human physiology and disease is far more nuanced. Yet the “theory of evolution” has largely remained unchanged - is it really only the fittest that survive? Humanity’s battle to overcome diseases such as cholera suggest the answer is more complex.

Cholera, caused by intestinal infection by the bacterium Vibrio cholerae, kills up to 150,000 people each year. The infection causes torrential diarrhoea; those who die cannot replace the lost water before their immune systems can fight off the infection. Infected individuals thus die from dehydration. The bacteria produce a disease causing agent, a "virulence factor'", that attaches to a protein on the outsides of cells in the intestinal walls. This protein, made by the "CFTR gene", is a gated passage between the inside of the cell and the intestines. The body has many genes that make such passages or "channels". They all allow small molecules to pass from the lumen of the intestine, where the food is normally, to the inside of cells, or vice versa. The CFTR channel normally allows only chloride (Cl-) ions to move from the intestine into the body. But when the virulence factor binds to the CFTR protein it reverses the direction in which the ions flow. Chloride ions exit the body, dragging water with them. This causes the profuse diarrhoea and dehydrates the patient, often fatally.

Our species has been evolving to overcome this disease. Generations ago, the CFTR gene of one of our ancestors made a chance mutation. This broke the CFTR channel and prevented it from opening, protecting the owner against cholera.  For these channels, no amount of virulence factors could induce them to let out chloride. Ultimately, when challenged by cholera, this person lost much less water and had a greater chance of surviving the disease. And by doing so, he or she was able to pass on this variant - or "polymorphism" - of the CFTR gene to his or her offspring.

Consider this now on the population level. Surviving cholera is obviously a huge evolutionary advantage: people who live to tell the tale are much more likely to have (more) children. And this is how the CFTR variant that protects against cholera has spread throughout populations, including among Western Europeans who have, historically, had very high incidences of cholera. This process of "positive evolutionary selection" means that many Western Europeans are "carriers" of this CFTR variant; they have one copy of the broken CFTR gene that protects against cholera and one normal copy that doesn’t.

Intuitively, you might think that people with two malfunctioning CFTR genes would be even better protected against cholera, but this is not the case. People who have two faulty CFTR genes actually develop a gruesome and fatal lung disease called "cystic fibrosis" because the CFTR gene is also found in the lungs as well as in the gut. In the lungs, the channel is involved in the production of mucus that helps keep the lungs clean and healthy. Without the export of chloride and its associated water, this mucus solidifies. Thick, sticky and inspissated, the mucus accumulates and clogs the airways, trapping bugs and encouraging repeated infections that progressively damage the lungs. Eventually this leads to respiratory failure in the majority of cystic patients. Sadly we still have no real treatment for the disease other than a lung transplant, although promising research into gene therapy to restore a working copy of the CFTR gene to the lung tissue is ongoing. But good quality care and medical advances have now also doubled the life expectancy of the average cystic fibrosis patient to 40 years.

Caucasians may have evolved genetic defences against cholera but they also have the highest incidence of births of people with cystic fibrosis: 1:3000. This "negative evolutionary selection" is why most Western Europeans are only carriers of the cystic fibrosis CFTR variant. Cystic fibrosis usually ensures that people who have two copies of the non-functional CFTR variant die before they can pass on their genes. At the other end of the spectrum, cholera selects for individuals with at least one copy of the variant CFTR gene. Ultimately this means populations end up with many individuals being carriers of the broken CFTR variant because this is most evolutionary advantageous state. These individuals are in the Goldilocks zone: they do not get cystic fibrosis and they are also protected against cholera.

Unfortunately for these Goldilocks individuals, if two of them meet, mate and reproduce, they have a one in four chance of having a child with cystic fibrosis. This is because evolution is still, and will always be, in progress. Our environments are extremely complex: advantages against one environmental challenge can destabilise our tightly regulated physiology, and lead to other illnesses and vulnerability to different diseases. Cholera and cystic fibrosis are by no means the only examples of this “balancing act” in evolution. People with only one mutated copy of the haemoglobin gene are protected against malaria whereas people with two copies get sickle cell anaemia. One faulty CCR5 gene significantly reduces the ability of HIV to infect the body. Two faulty CCR5 genes, however, increase your risk of gallbladder cancer. This Goldilocks style of evolution makes sense if you consider the human species as a single entity. Evolution keeps these genetic variants around in a population because they are useful under certain circumstances. Humanity is, essentially, hedging its bets. Five years after Darwin published his magnum opus, Darwin's contemporary, the biologist and evolutionist Herbert Spencer, summed up the entire work in one immortal sentence: "survival of the fittest". Maybe, a century and a half later, this statement should be revised. It seems it’s not so much the "survival of the fittest" that counts but instead the survival of the "least unwell"...

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