February Journal Club
I’m guessing that when most people think of the Tasmanian Devil, they think of this guy:
That loveable, cuddly (ok, maybe not so much) character from the Warner Bros. Looney Tunes cartoons.
The cartoon “Taz” had quite the appetite and left a path of destruction in his wake. His real-life cousins, the species Sarcophilus harrisii, are not so destructive or slobbery – and their particular taste for rabbits may not be clear – but they are carnivorous, speedy, and just about as cute.
And, unlike the Taz this will be forever immortalized in cartoon form, the real-life Tasmanian devils are doomed: Taz’s cousins are becoming extinct because of cancer.
More ferocious than the devil itself is Tasmanian devil facial tumor disease (DFTD). This cancer causes disfiguring tumors on the faces of Tasmanian devils and interferes with their ability to eat, so infected devils actually die of starvation and not from the cancer directly.
This cancer was first observed in 1996 and has quickly spread throughout the population of devils on the island of Tasmania, which is part of Australia. In 2006, a very important observation revealed the most unique characteristic of DFTD tumors: the tumor cells did not come from host animal.
Why is this so revealing? In most cancer types, tumors form because cells of the host somehow go awry. Even if something from the outside world causes the cancer (UV rays, smoking, human papillomavirus), the original source of the tumor is from the host, meaning that the DNA content of the tumor is the same as that of the host. Not exactly the same – there has to be at least one mutated gene otherwise it would be a normal cell and not a tumor cell – but close enough that if the DNA sequences of the host and tumor were compared, it would be clear that the tumor came from the host.
DFTD is different. In 2006, scientists found evidence that the DNA sequence from a tumor did NOT match that of its host, meaning the tumor cells had to come from elsewhere: another animal. And sure enough, the animals were giving each other cancer through the normal biting that occurs during mating and feeding. These tumor cells would essentially graft (stick) themselves onto the face of the victim of the bite and multiply there. The relative ease with which this occurs explains the rapid spread of DFTD throughout the Tasmanian devil population.
So, basically, DFTD is the vampire of the cancer world: it is immortal. Other cancers usually die with their host. Not DFTD: it lives on in the newly infected animals. Even though the first devil with the first case of DFTD has long since died (devils only live 5-6 years), that first tumor has essentially been cloned and started over with each new infection. As happens over time (think evolution), each clone may be slightly different than other clones due to random mutations, but all are variants of the same original tumor. To draw a comparison: when a human cancer metastasizes, or moves, it stays within the original host and moves from, for example, the breast to the lymph nodes. DFTD, though, metastasizes from one animal into another.
This property of being transmitted from animal to animal has wreaked havoc on the devil population but can also be used by researchers to study DFTD in the hopes of combating it. Instead of having to study this tumor in the lab, the devil population acts as a natural incubator, keeping the tumor cells alive indefinitely. By comparing the DNA sequences of normal devils to the sequences of present-day DFTD tumors, the following key questions can be studied:
1. What makes the tumor cells different than normal devil cells and how is it able to cause disease?
2. How has the cancer changed over time from the initial founder to the different lineages now found in nature?
3. How did the cancer spread from one devil to the entire devil population?
These are precisely the questions raised by a group of researchers when they set out to sequence the genome of the Tasmanian devil and different DFTD tumors (Murchison EP, et al. (2012). Genome Sequencing and Analysis of the Tasmanian Devil and Its Transmissible Cancer. Cell 148(4): 780-791).
How can sequencing the genome of an animal and its cancer cells reveal so much about the history of the disease and how it works? It all has to do with comparing different sequences and analyzing what must have happened over the course of time to cause these changes.
Three genomes were sequenced: a normal, adult female devil and two tumors from different parts of Tanzania (in the paper, these are called the titillating names of 87T and 53T). The two tumors have undergone random mutations since they diverged from the original DFTD tumor. By comparing these mutations to each other, researchers can estimate what changes occurred after the tumors left the original host. If both 87T and 53T have the same mutation in gene X, this mutation probably was in the original tumor because it is not statistically likely that both tumors would separately have the exact same mutation in the exact same place. (Consider these odds: if the tumor DNA genome is about 3 billion units in size, then the chance of an identical mutation in 2 different genomes is a 1/3,000,000,000 x 1/3,000,000,000 = 1 in 9,000,000,000,000,000,000 chance. Take those odds to Vegas!)
By identifying the mutations present in the tumors and not in the normal devil genome, the original tumor DNA sequence could be deduced. Then, by comparing the tumor genome to the normal devil genome, the differences that make the normal cells “normal” and the tumor cells “tumorigenic” were revealed. For example, mutations were found in genes that are related to cancer in humans. Also, mutations were found in genes that would allow the tumor to “hide” from the host immune system, a property it has to have to be able to survive on the face of a devil.
Once the researchers identified where the differences were in the sequences of the two tumor genomes, these “hotspots” could be identified in hundreds of tumors throughout Tanzania. A sort of family tree was constructed to trace the spread of DFTD from the original devil to its present widespread distribution – a history of the disease.
Understanding the past development of DFTD is academically interesting, as is knowing what the original tumor “looked” like, but there are further implications beyond just basic curiosity. By knowing how DFTD evolved in the past, scientists can predict how it may change in the future and act to target these changes to prevent or stop the disease. Furthermore, there are still ways in which the data from this study can be analyzed. For instance, even though mutations were found in certain genes, the “how” question has not been answered: how these mutations cause DFTD. So far, only genes that are known to play a role in human cancers have been probed for the presence of mutations, but others could possibly be involved.
DFTD is well on its way to causing the extinction of an entire species. Understanding how the tumor cells are different than normal cells is key for developing therapy to cure or prevent DFTD. One other cancer is caused in the same way as DFTD (that is, is immortally transmitted through bites): a cancer of dogs, called canine transmissible venereal tumor (CTVT). The lessons learned from DFTD may be relevant to CTVT. So, if the soft spot in your heart for Taz isn’t big enough, think of Fido.