Keeping up the pace

The world boasts a diverse range of weird and wonderful creatures, from butterflies, Salmonella and octopuses, to humans, mushrooms and Komodo dragons. All of them are the result of the fascinating process of evolution. More than 150 years ago, Charles Darwin proposed Natural Selection as the main driving force for evolution, which requires variation amongst individuals, trait inheritability and differential survival capacity. Evolution shapes life and it is gradual and slow. Well, not for everyone.

Some viruses have the ability to evolve at a remarkably fast rate. HIV, for instance, has an average generation time of 2.6 days and a very high mutation rate (1/10⁵ mutations per base per generation). This means that the genetic variation of HIV in one single infected individual is roughly the same as the yearly genetic variation of influenza within the entire human population (1). In contrast, we humans are very slow to evolve. With a generation time of 20-30 years and a high fidelity of replication (1/10¹⁰ mutations per base per generation), it’s not surprising that we struggle to defeat some of these little blighters. However, our immune system has a few time-tested tricks up its sleeve. One of our most precious weapons is antibodies.

Antibodies are Y-shaped proteins generated by a particular type of immune cell called B cells. They have the ability to bind pathogens in a strikingly precise and powerful way, thereby diluting their harmful capabilities. You are probably wondering how, when we are surrounded by a potentially limitless number of nasty creatures, could we generate antibodies against all of them? The answer is that, although our immune system does not know how to specifically design antibodies to target a certain kind of pathogen, it can fight fire with fire, developing micro-chambers of rapid evolution to combat disease.

Our limited number of immune genes can be combined in a virtually infinite number of combinations, like the way a deck of cards can be shuffled to generate an almost infinite number of poker hands. This random process results in billions of different antibody variants, which is a great starting point. But it’s not enough, and our bodies won’t stop there. We take these antibodies and test and tweak them to perfection.

The fine-tuning and perfecting of antibodies is hosted in dynamic microstructures called germinal centres. These originate in the tonsils, spleen, appendix and lymph nodes during immune responses to infectious organisms. Germinal centres are mainly comprised of B cells with a very special feature: their accelerated life and mutation rate. These B cells can divide about every 6 hours (the quickest ever seen in a human body) and mutate 100 times faster than HIV. Consequently, they incorporate abundant mutations that result in slightly different antibody variants. This means that like the pathogens they fight, antibody-producing B cells are capable of rapid evolution. So far so good, but we still haven’t addressed a fundamental part of the process: selection.

As with whole organisms, most new mutations are neutral or detrimental, only a few will confer advantage for survival. In the particular context of the germinal centre reaction, survival is dependent on the quality of the antibodies. In other words, the germinal centres must pick the appropriate B cells in a real-time Darwinian process. Another type of immune cell, the T follicular helper cells (Tfh), act as the effectors of selection. They are responsible for testing antibody-binding abilities and delivering survival signals to the best B cell candidates. At this point, the stakes are incredibly high. There is no room for mediocrity: either you match or you die. Tfh cells are scarce and B cells must therefore compete to get them. Like lions fighting for a limited amount of food, only the quickest, strongest and sharpest will be able to fulfil their needs and survive.

Humans change and adapt slowly, whereas viruses evolve rapidly, thus generating a huge challenge for our immune systems. Germinal centres appear in our bodies providing a microenvironment for high-speed evolution. This is a beautiful strategy that allows us to keep up the pace with such fast changing pathogens.

At the end of this process, our bodies possess B cells capable of producing efficient antibodies that are specific to the particular infection that ails us. If the pathogen mutates trying to evade our response, the chances are high that our B cells will also mutate, producing new and effective antibody variants. The arms race has started.

1. The Bulletin on AIDS Vaccine Research (http://www.vaxreport.org/Back-Issues/Pages/UnderstandingtheGeneticVariationofHIV.aspx)
2. Stop, Go, Evolve. Gabriel D. Victora. Science 2013.