Cancer has been with humans as long as they have existed. It’s likely to have been around even before we evolved, and it affects animals across the tree of life. Despite improvements in treatments and increased survival rates, cancer is still a huge burden, causing 9.6 million human deaths worldwide every year. Dr Alex Cagan, postdoctoral researcher in the Cancer, Ageing and Somatic Mutation Programme at the Sanger Institute, discussed his research into cancer and ageing in the animal kingdom at the American Association for the Advancement of Science (AAAS) conference in Seattle today. He is exploring what we can learn from species that are resistant to cancer, as well as those species with very long life-spans, and how we can apply that knowledge to preventing cancer in people. In the last 100 years scientists have come to appreciate cancer is a genetic disease, caused by DNA damage. Alex first described the genetic changes that cause a cell to become cancerous. “Every day our cells are accumulating huge numbers of lesions, from internal and external sources of DNA damage. Luckily our cells have an exquisite set of DNA repair mechanisms. Most damage is repaired and never makes it through; it doesn’t stay in the cell,” Alex explained. “But these repair mechanisms don’t have perfect fidelity. Occasionally, DNA damage stays in the cell, and is passed on as the cell divides.” These kinds of DNA changes, starting at birth and continuing over a lifetime, are termed ‘somatic mutations’. As a result, the cells in our body don’t each have an identical copy of our genome. Over the last 20 years, researchers at the Sanger Institute and others have discovered that we are ‘molecular mosaics’, made up of clusters of cells, each with slightly different DNA changes. “Most of the time, DNA damage and subsequent mutations occur in areas that aren’t functional – and so it doesn’t affect how the cell behaves. But every so often damage will hit DNA that is important, and affects how the cell functions,” Alex said. If enough of these mutations occur in one cell, then over time, the cell may transform. The mutations can cause the cell to eventually form a tumour that grows and spreads around the body. “We know a lot about somatic mutations in humans, but almost nothing about the process in other animals,” he explained.
Cancer across species
“We do know that other species get cancer. What is really interesting to me is that different species have very different rates of cancer – and as yet we have no idea why.” “The biggest mystery is massive animals. Given everything we know about cancer in humans, some larger species shouldn’t be able to exist.” “Whales, for example, have trillions more cells than us. If we take the somatic mutation rate from humans and apply it to whales, then they should, by chance, develop cancer even before they reach adulthood. But they don’t.” This apparent mismatch, that the rate of cancer doesn’t correlate with the number of cells in an organism, is known as Peto’s paradox.
“Large long-lived animals like whales and elephants make us question our assumptions about cancer and somatic evolution,” Alex said.
“Perhaps even more interesting is the process of ageing. It is a fundamental process – but we still know very little about the actual underlying causes of ageing. There are many theories and it probably involves many different processes, but one of interest to me is the somatic theory of ageing,” said Alex. “Potentially the accumulation of somatic mutations in our cells over time is causing a decrease in cellular function that leads to ageing. Looking at different species, with very different life-spans, is a good way to study this. We can ask if species accumulate somatic mutations at different rates. You might expect that longer-lived species have a slower rate of accumulating damage than shorter-lived species.” “And it begs the question, are cancer and aging two sides of the same coin? Are they both the result of the accumulation of mutations in our cells as we age?” To address these questions, Alex is working with London Zoo, the Natural History Museum and others across the UK to collect samples of species to study somatic mutation rates. He assured the audience that he is not taking cells or tissues from living animals – but they are collected by a zoo’s pathology team after an animal dies naturally. Once the samples arrive at the Sanger Institute they are fixed onto slides by the cancer histology team. Alex is studying cells from the colon of all these species, because cells from a tiny ‘crypt’ of the colon are genetically identical. This allows the team to get enough DNA for sequencing – and their results aren’t going to be confounded by mosaicism. Using laser capture microscopy, Alex cuts the a crypt from the cells. They fall into a plate waiting below and he then prepares them for sequencing.
The scientific operations team at the Sanger Institute sequences the DNA and returns the data to Alex. He compares the sequences between crypts, and between the crypts and a skin sample, to identify the mutations that are unique to an individual crypt – the somatic mutations. Alex shared his latest results. “What you can see in mice is an increase in somatic mutations over time. This is the same thing we see in humans. A 20-month-old mouse has a similar number of mutations to a 60-year-old human. We are seeing a strong and significant correlation between somatic mutation and lifespan across all the species we’ve looked at so far.” “Towards the end of an animal's lifetime, they tend to have the same number of mutations – whether that’s a mouse that’s lived for three years or a human for 80. That doesn’t prove one causes the other, but there is a link there.” “At the moment there is a lot we don’t know. That’s what’s so exciting. I’m particularly eager to get this information about longer-lived species like whales or tortoises. Are they accumulating somatic mutations? How are their cells avoiding damage?" “If we can find out, and use that knowledge to reduce the somatic mutation rate in people, we would have an effective way to prevent cancer.”
The DNA in our bodies accumulates mutations as we age. We are studying how this somatic mutation rate varies across species (including lions and tigers!). This may provide insights into cancer and ageing @sangerinstitute @OfficialZSL pic.twitter.com/sCgjk3xo7v
— Alex Cagan (@ATJCagan) January 23, 2020