Further reading for In Our Time Radio programme on Origins of Infection
11 Jun 2011A couple of days before my participation in the recent In Our Time programme I was given a list of questions that I was likely to be asked. On the day, the questioning deviated from the script and I didn't always get to say all I wanted to say on a given point. Here is a copy of the crib that I prepared before the programme, which I have marked up with hypertext links to relevant material for anyone interested in learning more about the topics we discussed.
(to Mark Pallen) Agents of infectious disease are known as pathogens – the best known are viruses and bacteria. Would you explain what they are and how they differ?
Well, the party line is that they are very different, which is why microbiologists get cross when people talk of the E. coli virus or MRSA virus, when both are bacteria!
Bacteria like us are made of cells, membrane-bound bundles of metabolism, DNA, RNA, protein and the wherewithal to make these molecules. We are multicellular, made of many different cell types, whereas bacteria are unicellular-for bacteria, generally the organism is the cell and vice versa. Our cells are also much larger than bacterial cells. Another important difference between our cells and those of bacteria is that we wrap our DNA up in a microscopic bag called the nucleus whereas in bacteria it hangs free in the cell. In the jargon, cells with a nucleus are called eukaryotes, cells without a nucleus are called prokaryotes and include bacteria and a third domain of life called archaea, which are small and unicellular like bacteria but only distantly related to them.
Viruses are not cellular life forms. When we bacteriologists want to disparage viruses, we call them infectious chemicals. They form infectious but metabolically inert particles that can survive outside of cells but to reproduce, viruses have to hijack cells. Some viruses hijack eukaryotic cells, some hijack bacterial or even archaeal cells. They key point is that they don’t have the machinery for making their own proteins; they have to rely on the host cell for that. They are also much smaller than bacteria and can generally be seen only with an electron microscope, rather than a light microscope.
But what I have given you is the standard answer. Over the last ten years or so the distinction between bacteria and viruses has become blurred, particularly after the discovery of a very large virus called Mimivirus, which was discovered in a water tower in Bradford in Yorkshire of all places. It was first thought to be a bacterium and even called Bradfordococcus, but a group in France showed that it is in fact a very unusual virus, with very large virus particles and a very large genome, both similar in size to bacteria and it remarkably it encodes some of the proteins used to make other proteins. This has led to a reappraisal of and new respect for viruses as a fourth domain of life that perhaps even predates cellular life forms.
(to Mark Pallen) Viruses and bacteria aren’t the only pathogens, though – what are the others?
Well at one extreme, smaller than viruses, we have prions, which really are infectious chemicals, in that they have no DNA or RNA genomes but instead appear to be misfolded versions of proteins normally present in the body. These misfolded proteins can catalyse misfolding of healthy proteins and eventually the accumulation of misfolded proteins can damage and even kill cells. There are very hard to destroy and can survive for long periods in the environment. The most famous example of a prion infection is BSE, or mad cow disease, as it is popularly known, and its human counterpart Creutzfeldt-Jakob disease or CJD.
Larger than bacteria, there are a number of groups of eukaryotic pathogens: fungi which includes infectious yeast-like fungi and moulds; unicellular eukaryotic pathogens, of which in global terms, the malarial parasite is the most important and then multicellular parasites, which include worms and so called ectoparasites, like lice, fleas and ticks.
Interestingly, there are two kinds of pathogens we do not see in humans : archaea never appear to cause invasive disease although they live in association with human tissues and might contribute with bacteria to disorders of the gut and periodontal disease. And we never see infectious cancers, although these have been described in some animals, particularly the Tasmanian devil, which is being decimated by Devil Facial Tumour Disease.
(to Mark Pallen) How can genomics help establish where a disease came from?
Well, in some case we can obtain ancient DNA from archaeological or museum specimens. Examples here include TB and plague. Using modern genome sequences we can often reconstruct the evolution of a human pathogen by comparing its genome to those of close relatives. One early surprise in the field concerns tuberculosis. There are strains associated with human and cattle infections, and in the past people speculated that the human disease might have originated from cattle, crossing over to human during the process of domestication. In fact, genomics has shown the opposite: the cattle caught TB from us!
Another example comes from the elegant work of Mark Achtman and others on the bacterium Helicobacter pylori that lives in the human stomach and is passed on in families. By looking at patterns of variation in the genomes of these bacteria from around the world they have been able to provide evidence for the out-of-Africa hyothesis, i.e. that all non-African humans are descendents of a small band of humans that left Africa 60-70 thousand years ago.
For many important bacterial pathogens of humans if we look back over periods of thousands of years, we see a pattern of evolution in which a lineage of a very generalist species of bacterium, that can live in many environments or on many hosts, becomes specialized to live in a much more restricted niche. During the process the organism starts to throw away parts of its genome that are no longer needed. This process of reductive evolution has happened for diseases like plague, anthrax, typhoid fever, whooping cough, where in each case the pathogen we see today is a cut-down version of its ancestor.
The most extreme example of this reductive evolution are the mitochondria, which live inside our cells and those of other eukaryotes functioning as energy-producing factories, but are in fact highly specialized bacteria, that entered such cells a billion years ago or so and have thrown away or outsourced 99% of their genomes.
(to Mark Pallen) What other information is hidden in the DNA of bacteria and viruses?
On a more recent timescale we can look at very small-scale differences between genomes to reconstruct chains of transmission of infection. For example, such an approach was used to find the source of the anthrax deliberately released into the US postal service. In fact we and others have used this kind of genomic epidemiology approach on a range of pathogens. Another interesting example come from studies on the genomes of leprosy bacilli from humans and armadillos in the southern United States suggest that humans gave armadillos the infection and then humans were catching the disease back from armadillos when skinning and eating them.
(to Mark Pallen) Some pathogens are much more likely to cause death than others. Would you explain the paradox of virulence?
Well, the paradox is why do pathogens damage and even kill their hosts when they depend on them for their own survival. Why would you burn your own house down?
There is no one-sits-fits-all answer to this question, but several answers that are not mutually exclusive but that all depend on Darwin’s theory of evolution. In some cases it is clear that causing disease provides an advantage to the pathogen in helping it get from one host to the next. For example, when a cold virus makes your nose stream and makes you sneeze, this is clearly helping spread the virus. For more severe infections, like cholera, one can see a trade-off, in that causing severe diarrhoea helps disperse the pathogen into the environment but at the risk of killing the host. But if the dispersal is effective, it may not matter some hosts die. But I have to say evidence for this hypothesis is still not conclusive.
In other cases virulence is harder to explain. Invading your blood to cause blood poisoning or your brain to cause meningitis doesn’t help spread the bacteria. But here, we can explain virulence as the result of short-sighted evolution that creates long term problems, because natural selection shows no foresight. So, for example, only a small fraction of the bacteria that can live in your throat can live in your blood or cerebrospinal fluid, but if they do spill over into these compartments natural selection will drive them to become better and better adapted to living, there. In addition, bacteria that get into deep tissues evoke host defences and inflammatory responses that generally help control infection but in some cases there is death or damage from friendly fire, as these responses damage the host.
Finally, some infections are best explained by Darwin’s principle of common descent, i.e. that all life is derived from a common ancestor and that organisms that superficially appear quite different in fact share common molecular toolkits in their cells and tissues. So for example, the bacterium that causes the kind of pneumonia called Legionnaire’s disease usually infects free living amoebae, but when aerosols from our hot water and air conditioning systems provide it with a route into our lungs, the bacterium simply treats our cells like unusual amoebae. And it can do this, because we and amoebae share a common ancestor.
(to Mark Pallen) Recent research seems to indicate that humans and their diseases have mixed their genetic material – how is this possible?
Well, viruses quite commonly steal genes from their hosts, particularly those that cause cancer. As mentioned mitochondria represent highly specialized descendants of bacteria that entered eukaryotic cells and have now been deeply integrated into those cells and have even transferred many of the genes into the nucleus. Many viruses can integrate their DNA into our genome and in fact our genome is littered with the remains of viruses that have jumped into the genome, have lost the ability to jump out again and are slowly decaying away, but also providing fuel for rearrangements and other changes in the genome. A few years ago some scientists manage to reconstruct the ancestor of some of these so-called endogenous retroviruses and showed that when they rebuilt its genome it produced infectious virus particles.
(to anybody) Can we ever hope for an end to infectious disease?
Well I am an optimist. It is interesting question that Steve and I could debate as to whether Darwin’s theory of evolution or the germ theory of infection developed in the decades following the publication of Darwin’s origin represents the greatest leap forward for humanity. I think this profoundly counter-intuitive theory, that infectious diseases are caused by microscopic organisms that we cannot see with the naked eye presents with such a profound step change that we cannot unthink it, we cannot imagine a world before this theory. And then there all the interventions that have flowed from it, including the development of safe water and sewerage systems, safe surgery, vaccines and antibiotics, safe sex etc,
And it is worth stressing that thanks to these interventions, we have already dramatically reduced the threat of infectious disease in Western societies and double life expectancies. OK, we still have a problem with hospital infection, but to put a positive spin on this, much of what we see here is the result of the heroic success of modern medicine in keeping vulnerable patients alive for long periods of time, when a generation or two they would have died before they could ever get infected. And the simple step of making the powers that be in the NHS more accountable for hospital infection has produced dramatic results.
On a global scale, It is important to recognize the dramatic successes in recent decades in disease control and for several infections, we are now contemplating eradication, for example polio, leprosy, river blindness or guinea worm and we have to thank bodies like the Gates Foundation, the Carter Foundation or the Rotary Club for this. These guys are not given the recognition they deserve as heroes in our fight against infection. And even with more intractable problems like TB and malaria there is new hope and some are even using the “E” word: eradication. We are winning and will win this fight.