Its not a tumour. Oh wait, it IS a tumour!

I admit it, I LOVE the movie Total Recall.  I love its cheesy special effects, I love The Governator pulling a bug out of his brain through his nose, and I love Sharon Stone in all her over-permed 80’s pant suit glory.  But most of all I love Kuato, the mysterious little conjoined-twin character who leads the Martian rebels in their fight against the Richter character (played by the terrifically melodramatic Michael Ironside) and his cronies.

Thing is, there are weirder things in the world than Kuato, and one of the all-time weirdest is a type of cancerous tumour called a teratoma.  Teratoma’s take the cake in my book for the strangest and most fascinating of all pathologies, and fish get really good ones, as you’ll see.

Typically, tumours arise when a cell in the body is transformed by a mutation that interferes with the normal cycle of cell growth and death that’s essential for regulating tissues.  Instead, the cell multiplies in an uncontrolled or inappropriate fashion.  These mutations are sometimes built into our genes, and sometimes caused by viruses, by contaminants in the environment, by radiation, or even by spontaneous mutations from mistakes in DNA replication.  Anyway, the type of tumour that develops depends on the tissue of origin, and there’s a whole taxonomy of names that describe them accordingly.  For example, a malignancy in the liver is a hepatocellular carcinoma, while a cancer of the pigment cells in the skin is a melanoma. 

But what happens when you get a tumour of a pluripotent or stem cell?  That is, a cell that hasn’t yet decided what to be when it grows up.  The answer is a teratoma.  What makes teratomas so cool and gross and awesome and weird is that as the cells in the tumour multiply, they can and do turn into other different cell types as they go, which is a perversion of the normal differentiation that stem cells would go through when they are maturing into a liver cell, a skin cell or whatever.  The result is a tumour that, at the tissue level, may resemble or contain one or more other tissues!  My colleague and pathologist extraordinaire Jeff Wolf introduced me to teratomas when I took the AQUAVET course at Woods Hole and I was horrified and fascinated.  I saw Jeff last week at the ISAAH meeting in Tampa and asked him if I could share one of his fish teratoma cases with you.  So here it is:

What you’re looking at is a very thin slice of the gonads of a medaka (a type of small fish thats used a lot as a model in biomedical research) stained with haematoxylin (blue) and eosin (pink), to reveal the structure of the tissue.  Ovaries and testes have a pretty high population of stem cells, so teratomas tend to be more common in gonads, but they can turn up anywhere that stem cells occur in the body.  Lets take a closer look, for those who may be unfamiliar with histopathology:

I outlined the tumour in yellow.  Most of the tissue surrounding it is gonad, and you can even see a few big blue oocytes scattered here and there, but you may also see how the tumour is sort of squishing the surrounding tissue.  But what’s cool is all that stuff inside.  The concentric structure marked 1, thats a bit of an eye - you can see the pigment layer of the retina and the alternating layers of rod and cone cells.  All that stuff marked 2 that goes from 12-4 on the clock face, thats all brain tissue.  The stuff marked 3, thats cartilage, and at 4, fish scales (the thin pink lines) and skin, complete with rows of mucus cells along the outside!  There’s just 4 or 5 tissue types in this lesion, but it could just as easily form a bit of gut, some pancreas or a bit of kidney, anything really.

How does this happen?  How can seemingly intact retina grow inside a tumour, a lesion whose very nature implies uncontrolled growth?  The answer seems to lie in cell-cell signalling.  As the first teratoma cell differentiated into a retinal cell, it sent out signals to surrounding cells to say “right lads, we’re forming an eye” and those cells fell into line as the lesion developed.  This is a normal process thats essential for proper development of embryos, but in a perverted recapitulation, we instead get bits of intact tissue forming in tracts within a tumour.  If you think its weird in a fish, wait till you see the ones in mammals: they can have bones, teeth, even fur, growing embedded within the tumour.

Teratomas: fantastically interesting and creepy, no?

This week: Eastern Fish Health Workshop

There's a special conference every year that's one of the best kept secrets in the fish world; its the Eastern Fish Health Workshop and this year its in sunny Shepherdstown WV, home of the National Fish Health Research Laboratories, which (as a quirk of history) are part of the USGS's Leetown Science Center.  I've been going ever since I came to America in 2000 and I just love it.  Why?  Well, its a combination of things.  Its small, usually around 100 people, which means you can spend some quality time with your colleagues. There's no concurrent sessions, so you aren't forced to miss anything, and there's also no poster sessions, which I consider to be largely a waste of time.  It covers a great diversity of topics - fish health in aquaculture, wild fisheries, coral health on reefs, aquarium animal health, crustacean health and mollusc sessions, as well as thematic sessions like immunology and chemotherapy.  There's no more diverse such conference annually, probably because its not affiliated with a scientific society that would limit scope.  The only meeting that comes close is the ISAAH, in Tampa later this year, and that only runs every 4th year.  But the best thing about the meeting is the people.  Perhaps as a result of its breadth of subject, it attracts folks of broad vision and diverse interests and I just love that.  I always leave energised by the people I meet and topics we discuss.  Indeed, one of my biggest current projects - metabolomics of whale sharks (more on that in future posts) - was inspired by an EFHW talk by Andrew Dacanay a few years back.

This year's conference is especially important because its the 35th anniversary!

So, I'll be in WV this week and will try to blog some about the talks as they happen.  This will mean writing from the Droid, so forgive me if things come across a little stilted.  Its an a amazing device, but its no substitute for a real computer.  It also means I might not do any blogging on peer reviewed research this week.  I'd like to think I'll be studious and go back to my room for that stuff, but there's more to be gained by picking someone elses brain.  Perhaps I'll post some interviews instead.

A Parasite a Day, keeps the Doctor in pay

My colleague Susan Perkins at AMNH has a most excellent blog that features a different parasite every day for a year.  Since the oceans have more parasites than anywhere else by far, many of her feature critters are marine.  Check out some of these marine beasties, then enjoy the rest of the collection.  There's a new one every day.

Crepidostomum cooperi - a digenean (fluke) parasite of fish
Nasitrema globicephalae - a digenean parasite of the sinuses of whales
Cyamus ovalis - isopod parasites often called "whale lice"
Maritrema novaezealandensis - an important model digenean from New Zealand mudflat animals
Polypodium hydriforme - a weird parasitic jellyfish relative that lives on sturgeon eggs, and:
Dolops sp., -  a type of Branchiuran (related to crustaceans) parasitic on piranha

Tilting the three-way tango - disease as a loss of diversity

Disease is a funny old thing.  We're taught from very early on that disease agents are "bad" and that, by contrast, the infected are somehow poor and unfortunate victims of nasty evil bugs.  This is clearly a cultural bias, wherein we project our own concerns about getting sick onto all other animals; there's no real reason to think that a bacterium or virus has any less right to be here or any less important role in the ecological processes of the world than does the dolphin it infects, or the fish or the lobster.  We have all survived eons while avoiding extinction, which makes us winners in the great game of evolution, the microbes every bit as much (or more) than their hosts.

Still, biases run deep.  This is important because sometimes they cloud our perceptions of whats really going on.  Consider coral diseases for a moment.  What, you didn't know that coals get diseases?  That's OK, neither did most folks, including many scientists, until fairly recently.  Lets picture a nice reef coral, maybe a handsome Porites, infected with one of the many "band"-causing agents (diseases that march across the surface of the coral, destroying tissue along a coloured front that gives the disease its name).  Most folks would perceive that the coral (good) was quietly minding its own business when it was "infected" by the microbe (bad), causing disease.  But actually it took at least three players to tango in this case; the coral had to be susceptible to the pathogen, the pathogen had to be infectious to the coral, and the environment had to set the scene that made the interaction swing in favour of the pathogen.  This simple "disease triad" is the most basic model of how infectious processes take place, but its just that: a basic model.

These days, disease studies are becoming a lot more nuanced, and its revealing a whole new world of how diseases start and stop.  Rocco Cipriano, a microbiologist colleague of mine at the National Fish Health Labs in Leetown WV, has been promoting a model lately where an infectious disease of fish (furunculosis) is caused by a disruption to the natural community of bacteria on the skin of fish; a community in which pathogens have no place normally.  The furunculosis agent (Aeromonas) is excluded from these communities by bacteria better adapted to living in normal fish skin and its associated mucus layer.  That is, until an environmental modulator, like a temperature spike or pollutant, shakes things up a bit; what ecologists would call disturbance.  And what is the first outcome of disturbance in most systems? Loss of diversity, in this case among the normal bacterial community.  Some bacteria disappear from the skin of the fish, freeing up resources (space, food) that are exploited by other bacteria - opportunists that can come in and pounce on the new space or food.  When that space and food consists of the fish itself, we call those bacteria pathogens.  This same process happens after any ecological disturbance, like a hurricane on a reef or a tree falling in a rainforest: opportunists come in and pounce on a newly-available resource; then as things settle down a succession takes place, until the early colonisers are displaced by more typical fauna.  In this view, disease is nothing more than a byproduct of disturbance and loss of diversity in the normal microbial community.

Which brings me back to corals and to the recent paper by Mao-Jones and colleagues in PLoS Biology.  These folks used a mathematical model to show that much the same holds true for the diseases of corals, which, like fish, rely heavily on a surface layer of mucus as their first line of defence.  It seems that in both corals and fish, the mucus is important, but even more important are the normal bacteria that live there, continually excluding pathogens and acting as a protective guard against disease.  In a very anthropomorphic sense, the corals (and fish) are using the surface bacteria as a biological weapon against the potential pathogens, at the expense of having to produce all that mucus for the bacteria to live and feed on.  Importantly, Mao-Jones and friends show us that the derangement of the mucus community can persist for a really long time after the initial disturbance.  This is important, because you often come along and see disease starting, but you may well have missed the initial insult that got the ball rolling, which may have occurred some time ago.

I really like this idea of infectious disease as an ecological disturbance and of many pathogens as simply early colonisers in the succession back towards health (or towards death, if the disturbance was too severe).  As a model, it doesn't work for everything, though.  There are many "primary pathogens" that are specifically adapted to invade healthy animals, but its not in the best interests of those organisms to invest so much energy in adaptations to invasion, only to kill the host, thus many of those are fairly benign.  For more "opportunistic" agents, however, I suspect it holds true much of the time, and that group includes many or most of the really virulent diseases.  I dare say many of the "emerging" diseases fall in this category, and we can expect to see more of this as the global climate continues to tilt the tango in favour of the pathogens.

Mao-Jones, J., Ritchie, K., Jones, L., & Ellner, S. (2010). How Microbial Community Composition Regulates Coral Disease Development PLoS Biology, 8 (3) DOI: 10.1371/journal.pbio.1000345