Cockles and Mussels, Alive, Alive-O!

And so they are across the globe, not forgetting clams, a term that can cover all bivalve molluscs – a huge number of species (over 15,000), all having a two-part, hinged shell. The body inside doesn’t have a backbone, making it soft and edible on a scale of keeping-you-alive to orgasmic, depending on the consumer – oysters and scallops are part of the family.

Bivalves are particularly common on rocky and sandy coasts where they potter happily along, generally burrowing into sediment although some of them, scallops for instance, can swim. By and large their only problem is that humans like to eat them.

Clamming up

However, it gradually emerged in the 1970s that there was another cloud hovering over some of these gastronomic delights. Their commercial importance had drawn attention to the fact that soft-shell clams living along the east coast of North America, together with mussels on the west coast and cockles in Ireland, were dying in large numbers. The cause was an unusual type of cancer in which leukemia-like cells reproduce until they turn the blood milky and the animals die, in effect, from asphyxiation. In soft-shell clams, also known as sand gapers and steamers, the disease has spread over 1,500 km from Chesapeake Bay to Prince Edward Island.

A 2009 study had shown that as the disease progresses there is a rise in the number of blood cells that have abnormally high amounts of DNA (in clams typically four times the normal number of chromosomes – i.e. they’re tetraploid). In parallel with this change the cells make increasing amounts of an enzyme called reverse transcriptase (RT).

That was pretty surprising as RT does what its name suggests: reverses part of the central dogma of molecular biology (DNA makes RNA makes protein) by using RNA as a template to make DNA. RT is usually carried by viruses whose hereditary material is RNA (rather than DNA – so they’re called retroviruses). As part of their life cycle they turn their genomes into DNA that inserts into the host’s genome – which gets reproduced (as RNA) to make more viruses.

But how did RT get into clams? Enter Michael Metzger and Stephen Goff from Columbia University in New York, together with Carol Reinisch and James Sherry from Environment Canada, who began to unravel the mystery.

Jumping genes

Using high throughput sequencing they showed that clam genomes contain stretches of about 5,000 bases that came about when the RNA of a virus was copied into DNA by RT (reverse transcriptase) and then inserted into the host chromosome. Normal clams have from two to ten copies of this ‘repetitive element’ that Metzger & Co dubbed Steamer. That wasn’t too surprising as we have repetitive DNA too – it makes up about half the human genome. Many of these repeated sequences can move around within the genome – they’re often called ‘jumping genes’ – and it’s easy to see how this can happen when RT uses RNA to make DNA that can then pop into new sites in the genome. And you might guess that this process could damage the host DNA in ways that might lead to disease.

A long jump?

It turned out that the diseased clams had suffered massive amplification of Steamer to the extent that they carry 150 to 300 copies of the sequence. So that’s about 30 times as many Steamer DNAs being scattered across the clam genome – but how could that cause the same disease all the way from New York to Prince Edward Island? The answer came from peering into the DNA sequences of the tumour cells: they were virtually identical to each other – but they were different to those of their hosts! Meaning? The damage that led to leukemia, caused by shoe-horning 100s of extra copies of Steamer into clam genomes, only occurred once. And the staggering implication of that finding is that the cancer spread from a single ‘founder’ clam throughout these marine-dwelling molluscs. The resemblance to the way the cancer spreads in Tasmanian devils is striking.

Fishier and fishier

Fast forward to June 2016 and the latest contribution from the Metzger group reporting four more examples of transmissible cancer in bivalves – in mussels from British Columbia, in golden carpet shell clams from the Spanish coast and two forms in cockles.

Each appears to cause the same type of leukemia previously found in clams. The disease appears to be transmitted ‘horizontally’, i.e. by living cancer cells, descended from a single common ancestor, passing directly from one animal to another. Indeed, if you transplant blood cells from infected animals into normal clams they get leukemia.

 Species hopping

All that is quite amazing but the genetic analysis came up with an even more bizarre finding. In the golden carpet shell clams DNA from cancer cells showed no match with normal DNA from this species. It was clearly derived from a different species, which turned out to be the pullet shell clam – a species that, by and large doesn’t get cancer. So they have presumably come up with a way of resisting a cancer that arose in them, whilst at the same time being able to pass live tumour cells on to another species!!

Cancer cell transmission between different species of shellfish. Cancer cells can arise in one species (pullet shell clams) that do not themselves develop leukemia but are able to pass live cells to another species (golden carpet shell clams) that do get leukemia (Metzger et al. 2016).

We have no idea how the cancer cells survive transfer. It seems most likely that they are taken up through the siphons that molluscs use for feeding, respiration, etc. and then somehow get across the walls of the respiratory/digestive systems. In the first step they would have to survive exposure to sea water which contains a lot more salt than cells are happy in. The ‘isotonic’ saline used in drips to infuse patients contains 0.9% salt whereas seawater, with 3.5%, is ‘hypertonic’ – cells put in a hypertonic solution will shrink as water is drawn out of the cell into the surrounding solution. Presumably the cells shrivel up a bit but some at least take this in their stride and recover to reproduce in their new host. Equally obscure is how a species can protect itself from a cancer that it can pass to another species.

These amazing findings throw a different light on the care-free underwater life depicted in Disney’s The Little Mermaid, in which the popular song ‘Under the Sea’ fails to mention floating cancer.

Can this happen to us?!!

Well, not as far as we know. But the fact that the known number of cancers that can be passed from one animal to another has now risen to nine does make you wonder. However, there’s no evidence that it happens in humans in anything like the normal course of events. There are examples of person-to-person transfer, notably during organ transplantation, and there is one recent case of cancerous cells from a tapeworm colonising a human host. But these are very rare, the latter occurring in a patient with a severely weakened immune system, and there is no example of spread beyond two people.

Phew! What a relief! So now we can concentrate on following developments both in Tasmania and beneath the waves in the hope that, not only can we go on satisfying our lust for clam bakes and chowders, but that these incredible creatures will reveal secrets that will benefit mankind.

References

AboElkhair, M. et al. (2009). Reverse transcriptase activity associated with haemic neoplasia in the soft-shell clam Mya arenaria. Diseases of Aquatic Organisms 84, 57-63.

Arriagada, G. et al. (2014). Activation of transcription and retrotransposition of a novel retroelement, Steamer, in neoplastic hemocytes of the mollusk Mya arenaria. PNAS 2014 111 (39) 14175-14180; published ahead of print September 8, 2014, doi:10.1073/pnas.1409945111.

Metzger, M.J. et al. (2015). Horizontal Transmission of Clonal Cancer Cells Causes Leukemia in Soft-Shell Clams. Cell 161, 255–263.

Metzger, M.J. et al. (2016). Widespread transmission of independent cancer lineages within multiple bivalve species. Nature 534, 705–709.

Muehlenbachs, A. et al. (2015). Malignant Transformation of Hymenolepis nana in a Human Host. N Engl J Med 2015; 373:1845-1852.