Whales and Cancer

One of the great things about Oxford really is that it often takes you less than a 10 minutes’ walk to listen to leading experts discussing their work. This happened to me a few weeks back when I went to Green Templeton College to see Sir Richard Peto, Professor for Medical Statistics and Epidemiology in Oxford, who used to work together with luminaries such as Richard Doll. Besides being a leading expert in his field and a strong anti-tobacco activist, Professor Peto coined a paradox named after him in the 1970s, addressing the observation that large animals do not experience an increased cancer risk, even though they outnumber species such as humans in cells significantly. All things being equal, more cells means more divisions, causing higher risk of mutations, leading to increased cancer risk. However, while 1 in 3 humans get cancer, just 18% of whales do.

Whereas some researchers reject the idea that there is a paradox at all, stating that the range of cancer risks across species is tolerable and might also be due to the lack of sufficient data, others believe that finding the solution to Peto’s paradox might give crucial insight into cancer-fighting mechanisms that could ultimately be used clinically. A relatively recent (Oct 2012) study by Roche, et al., from Montpellier in France mathematically modelled the evolution of protective mechanisms against cancer for animals of different weights based on their different numbers of cells. Two main types of cells in the genome of every organisms can, if mutated, give rise to cancer. The first type proto-oncogenes describes cells, and their mutated forms cause autonomous and uncontrolled cell division. Tumour-suppressor genes (TSGs), the second type of genes, normally prevent autonomous and uncontrolled cell proliferation, a feature that is lost when they are mutated.

Simply put, Roche et al.’s model defined the requirements for cancer to be mutations in both TSGs and proto-oncogenes. So, does evolution favour increasing numbers of TSGs, as that will indeed build up a massive security system against cancer? It seems not to be the case. Genes involved in such complex processes as tumourigenesis rarely have only one function. In their model, Roche et al. attributed decreased carrying capacity (fewer offspring) to an increased number of TSGs. For whales, for example, it is evolutionarily sensible to have a decreased number of offspring as long as they are well protected against cancer. Humans, on the other hand, would experience a general evolutionary disadvantage if they had more TSGs in their genome, as our reproductive fitness seems to be more important than protecting each individual from cancer.

The research team suggests whole genome sequencing for whales, elephants, and other large species as well as for smaller species that show a generally decreased risk of cancer, such as the naked mole rat. This could indicate crucial mechanisms of cancer supression, which could, in the long run, may even be used clinically.

Although a riveting field of research, I doubt that it can jump from an area of evolutionary understanding of the disease right to the clinic for practical applications. Even if a unique set of TSGs would be identified to be conserved over certain relatively cancer-resistant species, how could this serve us? Maybe a systemic change of our proteome could prevent our cancer from growing; it may even be commonplace one day that during preimplantation genetic diagnosis every genome of a person-to-be will be “upgraded” by inserting the respective genetic sequences. However, it is not even clear whether looking for distinct distributions of TSGs in different species is the correct starting point when trying to solve Peto’s paradox, with some researchers claiming that the differences in metabolic rates between large (slow) and small (high) animals are the cause of distinct cancer risks. We should wait until whole genome sequencing of and comparison between different species is completed and so that we actually have data.