The inefficient consequences of evolution

Vertebrates are unique in developing an immune system capable of anticipating pathogens that are yet to evolve. Birds and mammals have taken this "adaptive" immune system to the pinnacle, with T cells and B cells using a randomised form of genomic engineering. The advantage of a system based on randomised generation is striking - by making every T cell and B cell unique it becomes exceptionally difficult for pathogens to "out-evolve" their hosts. Regardless of how a pathogen will change, pre-existing T cells and B cells will be capable of recognising the new modified pathogen. The importance of the adaptive immune system to humans is evident in the fatal consequences of its absence, such as patients with end-stage AIDS or primary immunodeficiencies caused by genetic mutations. These benefits greatly outweigh the cost of the adaptive immune system in resources used and the threat of autoimmune disease.

But does the adaptive immune system make vertebrates more healthy? There is no obvious evidence that it does. In a key essay on the topic, Hedrick argues that vertebrates do not appear to have a lower pathogen-induced mortality rate than invertebrates. Instead, he argues that the development of the adaptive immune system provided only a short-term benefit, with pathogens rapidly being specialised to vertebrate hosts. The result is an immunological arms race, with each side incrementally ratcheting up the armaments. Vertebrates are essentially impervious to non-specialised pathogens unless rendered immunodeficient, but the additional mortality from specialised pathogens is probably equivalent to the invertebrate state.

This still-controversial hypothesis high-lights an important aspect of evolution by natural selection. It has highly inefficient consequences. Natural selection takes place at the level of the individual and evolution takes place at the level of the species. Most importantly, natural selection only occurs in the present. An individual who has an advantage for even a single generation will be over-represented in the next generation. A species that has an advantage for a single generation will be able to exploit more resources for reproduction. The long-term consequences - that each species will waste more resources in an ever more expensive battle - is irrelevant.

The evolutionary arms-race between host and pathogen is one incredibly important example. A more illustrative example of the patent futility of this arms-race comes from Sir David Attenborough, one of the leading science communicators of all time. In Life in the Undergrowth, he films two species of harvest ants living in the desert. Each population needs to collect seeds to survive, however the number of seeds produced in the desert is so low that there is fierce inter-species competition. One species of ant is diurnal, the other nocturnal, and each is capable of collecting the entire daily seed dispersal. In order to survive, every second night the nocturnal ants spend an evening carrying rocks to cover the entry hole of the diurnal ants. The diurnal ants can't collect seeds the next day as they need to spend a day clearing the rocks from the entrance. This gives the nocturnal ants a night to harvest the uncollected seeds. The following day the diurnal ants are able to collect every seed and that night the nocturnal ants spend carrying rocks. Two species end up literally carrying rocks backwards and forwards every second day.

The elegance of evolution is the beauty of such specialised behaviour, but the consequences are gross inefficiency in resource use. If each species simply spent alternative cycles conserving resources both species could survive with a higher population density than currently exists. But neither species can be the first to stop the wasteful use of resources, as that would give a fatal advantage to the other, and so they are trapped together in a cycle of carrying stones. The battles of night ants vs day ants and of hosts vs pathogens illustrate the bizarre, elaborate and ofttimes perverse consequences of evolution by natural selection

A time-line for diabetes research

6th century BCE – The first known diagnosis of diabetes was made in India. Doctors called the condition medhumeha, meaning "sweet urine disease", and tested for it by seeing whether ants were attracted to the sweetness of the urine.

1st century CE – Diabetes was diagnosed by the ancient Greeks. Aretaeus of Cappadocia named the condition διαβήτης (diabētēs), meaning "one that straddles", referring to the copious production of urine. It was later called diabetes mellitus, "copious production of honey urine", again referring to the sweetness of the urine. Unlike the Indian doctors, Greek doctors tested this directly by drinking a urine sample. At the time a diagnosis of diabetes was a death sentence: "life (with diabetes) is short, disgusting and painful" (Aretaeus of Cappadocia).

It is probably that the ancient Egyptians and early Chinese cultures also independently discovered diabetes.

10th century CE - Avicenna of Persia provided the first detailed description of diabetes (diagnosed through "abnormal appetite and the collapse of sexual functions" as well as the "sweet taste of diabetic urine"). He also provided the first (partially) effective treatment, using a mixture of lupine, trigonella and zedoary seed.

1889 – Joseph von Mering and Oskar Minkowski in Germany developed the first animal model of diabetes using dogs, discovering the role of the pancreas.

1921 - Federick Banting and Charles Best in Canada first cured canine diabetes by purification and injection of canine insulin.

1922 - For the first time diabetes stopped being a death sentence. In 1922 Federick Banting and Charles Best treated the first human patient with bovine insulin. Notably they decided to make their patent available globally without charge.

1922-1980 - Treatment of patients with animal insulin or human insulin extracted from cadavers. Substantial life extension but also significant side-effects.

1955 - Determination of the protein sequence of insulin by Federick Sanger in the United Kingdom.

1980 - First commercial production of recombinant human insulin, by Genentech.

Today there is no cure for diabetes, but when treated it only results in an average loss of 10 years (the same as smoking).

Infectious cancer

It has long been known that the several causes of cancer are infectious. Typically a virus contains a number of oncogenes to enhance its own proliferation, and in an infection gone wrong (for both virus and host) a viral oncogene is incorporated into the host DNA, creating an uncontrollable tumour cell. One of the best examples of this is human papillomavirus (HPV), a virus which infects most sexually active adults and is responsible for nearly every case of cervical cancer worldwide (which is why all girls should be vaccinated before they become sexually active).

However these cases are not "infectious cancers", they are infectious diseases which are capable of causing cancer. True infectious cancers, where a cancer cell from one individual takes up residency in a second individual and grows into a new cancer, were unknown until recently. With the publication of a new study in PNAS we now have three examples of truly infectious cancers.

1. In the most recent study, researchers in Japan documented the tragic case of a 28 year old Japanese woman who gave birth to a healthy baby but within two months had been diagnosed with acute lymphoblastic leukemia and died. At 11 months of age the child also become ill and was diagnosed with acute lymphoblastic leukemia. Genetic analysis of the tumour cells in the baby demonstrated that the tumour cells were not from the child herself, but rather maternal leukemia cells that had crossed the placenta during pregnancy or childbirth and had taken up residency in their new host. With this information, retrospective analysis indicates that this is probably not a one-off event, and at least 17 other cases of mother-to-child transmission of cancer have probably occurred.

2. In addition to mother-to-child transmission of cancer, cancer can spread from one identical twin to another. Identical (mono-zygotic) twins have identical immune systems, preventing rejection of "transplanted" cells, unlike non-identical (di-zygotic) twins. Thus a tumour which develops before birth in one identical twin can be transferred in utero to the other identical twin, where it can grow without being rejected. In one improbable but highly informative case, a set of triplets were born where two babies were identical and the third was non-identical. A tumour had arisen in one of the identical twins in utero and had passed to both other foetuses, but had been rejected by the non-identical foetus and accepted by the identical foetus. Of course, with the advent of medical transplantation, transmission of infectious cancers is now no longer limited to the uterus. Transplantation of an organ containing a cancer into a new host can allow the original cancer to grow and spread, as transplantation patients are immunosuppressed to prevent rejection. There is also a single case of a cancer being transmitted from a surgeon who cut his hand during surgery to a patient who was not immunosuppressed.

3. In a medical mystery well known to Australians, the population of Tasmanian Devils has been crashing as a fatal facial tumour has been spreading across the population. The way the fatal tumours have spread steadily across Tasmania and sparing Devils on smaller islands first suggested a new infectious disease that causes cancer, similar to HPV in humans. However a suprising study demonstrated that the cancer was directly spreading from one Devil to the next after having spontaneously developed in a single individual. These scrappy little monsters attack each other on first sight, biting each other's faces. The cancer resides in the salivary glands and gets transmitted by facial bites to the new Devil. Unfortunately for Tasmanian Devils, a genetic bottleneck left all Devils so genetically similar that they are, for immunological purposes, all identical twins. This means that the cancer cells transmitted from one Devil to another through biting are able to grow and kill Devil after Devil. The cancer from a single individual has already killed 50% of all Devils, and it is possible that we will have to wait until the cancer burns out by killing all potential hosts before reintroducing the Devil from the protected island populations. As unlikely as this seems, another similar spread occurs in dogs, where a cancer that arose in a single individual wolf is being spread through sexual transmission from dog to dog around the world. This example also illustrates the point made about cancers being "immortal" - the original cancer event may have occured up to 2500 years ago, with the tumour moving from host to host for thousands of years without dying out.

Recreating the thymus

I am writing today from the European Congress for Immunology in Berlin. A talk by Thomas Boehm was the highlight of the first day for me.

The Boehm laboratory has been looking at the genetic evolution of thymus development. The thymus is the nursery for T cells, the coordinator of the adaptive immune response. The Boehm laboratory analysed the genetic phylogeny of sample species spanning the 500 million years of thymus evolution and found several key genes that have been conserved through this process. The master coordinator of thymus development, Foxn1, had already been known, but how this master coordinator worked was a mystery, so the Boehm laboratory used the evolutionary analysis to try to recapitulate thymic development in zebrafish and mice.

In zebrafish, Weyn and colleages were able to use live imaging to analyse the genes that the thymus needs to express in order to recruit progenitor cells. This was done by using genetic expression of coloured dyes, making the primordial thymus glow red and the progenitor cells glow green. They found that just two conserved genes, Ccl25a and Cxcl12a, were synergistically acting to draw in all the precursor cells.

In mice, Bajoghli and colleages tried to use the knowledge gleaned from evolutionary analysis to completely bypass Foxn1. The rationale is that if we know exactly what Foxn1 does to drive thymic development then we should be able to recapitulate thymic development in the absence of Foxn1 by simply expressing the downstream genes. So the Boehm team took the four key genes that were conserved over 500 million years of thymic development, Ccl25, Cxcl12, KitL and Dll4, and expressed them in isolation or in combination in thymic cells that were genetically deficient in Foxn1. Normally, these deficient thymic cells cannot attract T cell precursors. However, Bajoghli and colleages found that just as in zebrafish, two genes in mice were able to essentially restore the capacity to recruit precursors, Ccl25 and Cxcl12. A third gene, KitL, allowed these cells to proliferate and increase in number. What these three genes could not do, however, was turn the precursors into T cells. That job required the fourth gene, Dll4, which had no role in recruitment or proliferation but which was essential for the differentiation of recruited precursors into T cells. Through evolutionary genetics the gene network of an entire organ is being unravelled.

Some of this research is current unpublished, other aspects just came out in the journal Cell.