Keeping up with the Red Queen: Co-evolution of hosts and pathogens

While most micro-organisms are harmless to humans, and in some cases even beneficial, there are those that are not welcome. These are known as pathogens, from the Greek for ‘producer of suffering’. For us, pathogens can be very damaging and even deadly, and so we have evolved ways to resist their attacks. For the pathogen, infecting a human might be the only chance to survive and reproduce. The potential reward is so great that pathogens will develop ways around our defences. This becomes an ongoing battle and means that neither side can stop evolving in case the opponent becomes too dominant; in the words of the Red Queen from Lewis Carroll’s Through the Looking-Glass: “It takes all the running you can do, to keep in the same place.” This interplay between host and pathogen is known as co-evolution and can lead to very different strategies being used on both sides.

The Red Queen (not to be confused with the Queen of Hearts) and Alice

All-out war

Aggressive strategies, like that used by the malarial parasite Plasmodium falciparum, can drive co-evolution rapidly. Once it has infected a person, the pathogen replicates as quickly as possible. This is risky because it seriously affects the infected human and can even cause death, and if the host dies, the pathogen die with it. This strategy works because P. falciparum spreads between humans via mosquitoes. High concentration of the parasite in the bloodstream is the best way to ensure that they are taken up by a mosquito and passed on to a new host. However, the severity of malaria and the high likelihood of death means there is a strong evolutionary pressure for humans to develop resistance, even if that comes at a price.

Indeed resistance has developed, via a specific mutation in the gene coding for the blood protein haemoglobin. Everyone has two copies of the haemoglobin gene – one from each parent. A mutation in both copies of the gene provides malarial resistance but causes sickle cell anaemia. This causes blood flow to be restricted and eventually leads to premature death, which obviously outweigh any benefits. Fortunately, having just one copy of the mutation maintains some resistance and avoids sickle cell anaemia. However it can never be guaranteed that a child will inherit exactly one copy of the mutated gene, so there is always a risk of children being born with sickle cell anaemia. This means that the level of the mutation present in the population is determined by the balance between the risk of malaria and the risk of sickle cell anaemia. There is little risk of malaria in the UK and so the mutation is rare. In sub-Saharan Africa, where malaria causes a quarter of all deaths in children under five, the balance shifts. The mutated gene is present in up to 40% of the population, meaning that approximately 2% of children are born with sickle cell anaemia.

When a specific glutamic acid residue (highlighted in magenta on the far right) is mutated to a valine it causes haemoglobin molecules to aggregate, which distorts the shape of red blood cells

Under the radar

Evolving against every new infectious disease that we encounter is not possible. Humans, with our relatively slow reproductive rate, take a long time to develop new, beneficial mutations. This is why many infections, such as the common cold caused by the rhinovirus, have evolved to avoid affecting humans severely. Catching a cold will not affect the ability to reproduce, which is the main driving force behind evolution. Without this evolutionary pressure, humans do not appear to have developed mutations to specifically deal with the rhinovirus. Keeping the host able and mobile also has the benefit of boosting the spread of the disease. If the host feels well enough to leave bed and go to work, then the rhinovirus is presented with a wide range of potential hosts with every sneeze.

The immune system provides a flexible defence against a huge variety of diseases, lessening the need to evolve in response to new infections. The system learns to recognise a part of the pathogen known as the antigen, which allows the pathogen to be targeted. This means that a strain of rhinovirus, or any pathogen, that has mutated its antigen can evade detection by the immune system for longer. Unfortunately for us, this happens very often as the rhinovirus mutates very easily and reproduces incredibly quickly, allowing a huge number of mutations to accumulate within a population rapidly.

Gaining ground

Today the risk of dying from an infectious disease is lower than at any point in human history. After thousands of years locked in an impasse with diseases, we have finally developed an advantage through modern medicine. Although it seemed that we have surpassed the power of evolution, pathogens are still working towards breaking through our defences. Whether it is a new strain of flu or an antibiotic-resistant superbug, if we want to maintain our advantage it will take all the running we can do.

Note: this post was updated 16:53 GMT 21/10/2012 to remove any suggestions that Plasmodium falciparum is a bacterium



2012 Nobel prize in chemistry: G protein-coupled receptors

I couldn’t let today pass without writing something about the Nobel prize. Before long I’ll write a full piece about G protein-coupled receptors (GPCRs) but that’s quite a big story. For now, I just want to stress their importance and their place in current research.

A cell requires isolation from the outside world; maintaining different concentrations of ions inside and outside the cell is a vital part of how it functions. GPCRs play a hugely important role in detecting signals sent from outside the cell and relaying them to the inside. They are known as trans-membrane proteins because they extend from outside the cell, through the membrane and into the inner region. This means that when they bind a ligand on the outside of the cell (e.g. a hormone), the resulting structural rearrangement can trigger a chain of signals through to the inner machinery of the cell.

Beta-2 adrenergic receptor

Beta-2 adrenoceptor, the first structure of a human GPCR. It was solved by Brian Kobilka’s lab in 2007. The red portion indicates the membrane-bound section and the green indicates the intra-cellular section [the extra-cellular region was not observed].

Trans-membrane proteins are poorly studied, largely because it is so difficult to keep them stable when studying them in the lab. The parts of the protein that are outside the membrane will have positive and negative charges pointed outwards, interacting with water molecules. However, the membrane is made from fatty chains that repel water and so the region of the protein that stays in the membrane will be structured in a way that avoids water by having its hydrophobic amino acids pointing outwards. Keeping both of these regions stable in the same solution is tricky, but manageable. Detergents can mimic the membrane and are widely used.

Detergents can make it difficult to study the structure of GPCRs. Most protein structures are solved using X-ray crystallography or nuclear magnetic resonance (NMR). However, crystallography requires all the protein molecules to be very uniform which is difficult with the added complexity of a detergent that may form different shapes and sizes. NMR begins to lose its sensitivity as the size of the protein increases. In this case, the detergent counts towards the protein’s size which makes it difficult to get data.

This has meant that despite the huge importance of GPCRs in biochemistry and medicine (over a third of all drugs act via GPCRs), our understanding of them is still relatively poor. However we would be a lot further behind if it wasn’t for Lefkowitz and Kobilka – they are very deserving Nobel laureates.

Magnetic trigger for cancer death

A team of researchers from Seoul have developed a magnetically-controlled nanoparticle that can kill cancer cells.

One of the key challenges in the fight against cancer is that potential treatments can often be worse than the disease. These treatments are so destructive that it takes a lot of effort to find one that will kill the cancer before it kills the patient. This means that treatments need to be as selective and controllable as possible.

The nanoparticle can be controlled by simply turning a magnetic field on and off. This means that its effects can be aimed at a specific area (if you have a focused magnetic field) and for a specific length of time. This level of targeting would reduce the severity of side-effects, allowing patients to receive stronger doses.

The zinc-doped iron oxide nanoparticle is attached to an antibody which binds tightly to death receptor 4, DR4. There are many copies of DR4 on the surface of the cancer cell and the nanoparticles can bind to them all, without any effect. When a magnetic field is applied, the nanoparticles move towards one another across the cell surface. This causes the DR4s to come together to form a complex. This is known as death-inducing signalling complex and it starts the chain reaction of events leading to apoptosis (programmed cell death).

Antibodies bind very specifically to their target protein, making them very useful in medicine

This mechanism is actually a mimic of the one used by the TNF-related apoptosis inducing ligand (TRAIL). TRAIL has been investigated as a cancer treatment, however it degrades easily, a problem that is unlikely to affect the nanoparticles.

The paper, published in Nature Materials, looks at the effect on cancer cells in vitro and the effects on zebrafish. This research is still very much in the early stages and it will be quite some time before its effects on cancer in humans can be tested. However, it is a fine example of the novel ways that scientists are trying to fight cancer. It is the trickiest disease there is, and it will take a lot of ingenuity to tackle it.

…and this little piggy corrected genetic mutations

Scientists have come a step closer to being able to correct mistakes in our DNA, thanks to a new method for rewriting mutations in stem cells. This could be used to treat genetic diseases for which there are no treatments available.

The researchers made use of piggyBac, a ‘jumping gene‘ originally found in moths. These ‘jumping genes’, as their name suggests, move from place to place along the DNA and can be used to carry other genes with them. Acting as a genetic cut-and-paste, they can neatly insert a corrected gene with remarkable precision. “Our systems leave behind no trace of the genetic manipulation, save for the gene correction,” says Professor Allan Bradley of the Wellcome Trust Sanger Institute.

In the case described in Nature the team focused on a genetic liver disease.

Severe deficiency in the protein alpha 1-antitrypsin is caused by a mutation, which is found in 1 in 2000 North Europeans. This protein is produced in the liver, but is responsible for protecting the lungs. The mutation causes the protein to accumulate in the liver, leading to cirrhosis, and deplete in the lungs, causing emphysema.

The scientists converted samples of patients’ skin cells into stem cells and corrected the mutation, using piggyBac. These stem cells were then converted into liver cells, in test tubes and in mice, which were able to produce the correct form of the protein.

Despite advances in the technology, producing stem cells in this fashion introduces new mutations into the DNA. While most of these mutations are likely to be harmless, there can be potentially fatal side-effects. This risk will need to be minimized before the technique is brought forward to treating patients.

Currently the only cure for alpha 1-antitrypsin deficiency is a liver transplant, but with transplant waiting lists longer than ever, this new development can bring hope to thousands of sufferers.