eLife episode 29: Microbiome mind control, epilepsy and parastic worms

CTVT, or canine transmissible venereal tumour, is very unusual kind of cancer. The majority of cancers we see arise from an individual's own cells. But in this dog tumour, which emerged in one single dog 11,000 years ago, the cells from that animal's cancer are infectious and they can spread to other dogs, causing genital and facial tumours, when the animals mate. Now scientists at Cambridge University have studied dogs with the cancer from around the world, turning up a big surprise: the cancers have adopted DNA from the host dogs they've infected. Specifically this has happened in structures inside cells called mitochondria, which provide cells with their energy and this is how the tumour keeps fit. Georgia Mills went to see researchers Andrea Strakova and Máire Ní Leathlobhair at the department of veterinary medicine...

Andrea - We looked at CTVT tumours from different parts of the world. So we collected over 400 samples from 39 countries around the world and we looked at the mitochondrial DNA of these samples. So mitochondria are let's say, batteries of the cell which provide energy. They have a small piece of DNA which codes for the proteins needed by the mitochondria. We looked at the mutations or genetic changes in this mitochondrial DNA which gave us a unique opportunity to look at the ways that the disease spread around the world.

Georgia - Because these cancer cells are transferred directly from dog to dog, cells in each tumour are from the original dog to contract it 11,000 years ago. Meaning, it can be traced back to that time. But very occasionally throughout history, a tumour in a specific dog has done something a little unusual and grabbed mitochondrial DNA from cells of the host dog.

Máire - My name is Máire Ní Leathlobhair and I'm a second year PhD student in the Transmissible Cancer group. We were able to use the kind of phenomenon of horizontal transfer in CTVT cells as a kind of cellular tracking device. If you can imagine that usually, dogs would carry around their own normal mitochondria but these host mitochondria then swapped into the cancer cells and these were spread throughout global dog populations over hundreds to thousands of years. Using these and kind of the patterns we saw across our global population of samples, we're able to track how different groups of dogs afflicted with CTVT moved.

Georgia - This snatching of DNA happened at least five times in history. Meaning, the team could get a clearer idea of the movement of infected dogs throughout time. This pattern matched old trade routes across the ocean. So, it looks like people took their dogs with them to the high seas. Andrea...

Andrea - So, from the five different transfers of mitochondria, we were able to define five different clades. The timing of these clades was based on the mutations which we found in each of the mitochondria.

Georgia - By working out the just normal background rate of mutations, you can look at these, you can take the DNA from the dogs that are infected, look at the DNA in the mitochondria and then find out how old this cancer is.

Andrea - Exactly, because we used a so-called molecular clock so we can look at the number of mutations which we see in each of these different mitochondrial types. That helps us to look at the timing when each of them arise.

Georgia - And then these different clades are from when these big events, when mitochondrial DNA switched.

Andrea - Exactly. So, these are from the time when the mitochondrial DNA from the dog actually jumped into the tumour cell and this was the switch as you described.

Georgia - Why would this happen?

Andrea - Well, we think one of the reasons could be that the mitochondria in the tumour have so many mutations that they would be in a way less functional. And therefore, gaining mitochondria from the normal dog, that would provide a selective advantage for the cell.

Georgia - By grabbing this mitochondrial DNA from healthy dogs, they can reduce the number of harmful genetic changes that will have built up over time - a very clever trick. But the team came across something even more surprising.

Andrea - Well, we found one very, very special case in a dog in Nicaragua. What actually happened in this dog is that not only that the mitochondria jumped from the dog into the tumour cell but actually, we found that these two mitochondria mixed to create a single mitochondria formed both by the tumour and the dog DNA.

Georgia - Why is this unusual?

Andrea - This is something that has never been reported in cancers before. We believe this could be because it may be very difficult to detect. So we suspect that this process could actually be a lot more common than expected but we just don't have the tools to detect it. So, what we are planning to do in the future is to look more widely to see if this type of mitochondrial mixing is found in other tumours around the world. And also, it would be very interesting to see if we can see this type of mixing in human cancers as well.

Georgia - Do you think this would have any implications for cancer treatment?

Andrea - If mitochondrial recombination is indeed common in human cancers as well then certainly, they would be a potential for targeted treatment.

A criticism often levelled at undergraduate science degrees is that a lot of spoon feeding goes on and there's not enough emphasis placed on acquiring practical skills and the ability to think "outside the box". These are critical assets for a successful scientific career, particularly when it comes to the emerging and fast moving field of molecular biology. So why do we often wait until a student embarks on a PhD before giving them the chance to discover whether they really are cut out for this line of work? Yaniv Erlich has taken this DNA bull by the horns and set up a special class for his students at Columbia University where they were given a mobile DNA sequencing device and told to decode what was in a postdoc's dinner...

Yaniv - Our idea was to let the students have hands-on experience with DNA sequencing technologies. Part of this class was that Sophie, my post-doc left a DNA from her food over a week. And she prepared DNA libraries and gave it to the students. They used these mobile DNA device to sequence the DNA from her food and they had to guess. They had to find what she ate. The whole concept here was to show them end to end how to generate, analyse, and infer results from DNA experiments.

Chris - Why did you decide to launch on this particular topic in the first place? Why do this?

Yaniv - The vision that we and others share is that we're going to see this era of ubiquitous DNA sequencing. So we want to have the students a glimpse to the future and also to train them in a way that they will help us to bring this future so they can think what they can do with this device. They can really realise the potential of this device by touching and playing with it writing some software to analyse its data and so on.

Chris - How did they respond? How did it go down with the class? Did the students take to it?

Yaniv - Yeah. So the students were highly enthusiastic about the class. I have to admit this is the first time that I'm teaching so I was a bit nervous before the class started in general. But the feedback was just fantastic. They love this class. They appreciated that we exposed them to an early on technology. One thing that was interesting to see, they are used to technologies that are near perfection. Let's say, cell phones or their operating systems on the computers. Now, this device is not yet perfected. There are still some gaps. They need to find work around, they need to tinker. It was interesting to see how they react to something that is not yet perfected, is not in a production grade I would say. But they're engineers and it's part of their training - is really to see things at an early stage and to think how they can evolve them, how they can help to mature this device, and how they can find work arounds.

Chris - I suppose in that respect, it's quite a nice prelude to what to expect from a career in science where people don't hand you a solution on a plate like they often are criticised for doing during an undergraduate degree.

Yaniv - Exactly. We got a feedback from some of the students that this is the first time that they feel in their undergraduate degree that they do science.

Chris - So that was what they learned. What did you learn and how does this inform what you do next with this project?

Yaniv - So, we learned how to design this experiment and how to engage the students. You can get quite a lot from a group of undergraduates and masters students that are highly enthusiastic about the devices. In the second Hackathon that was done around - the main topic was forensics, we in fact, started a research project in my group after the results of one of the Hackathon groups with the device. They came up with a very interesting algorithm and we said that this might be a research project so we should take on and really expand these preliminary leads that they found in the class.

Chris - Big trend now though to take things even lower and further down than that undergraduate level and people are talking about going into schools with this kind of thing. Do you think this is the kind of thing that could be used to encourage even younger learners, people before they've even gone to university to show them what they could be doing scientifically and then nurture more of that scientific spirit so we get more people going to university to study science?

Yaniv - Yeah. I think this device had a potential to go to schools. The main challenge is to create a curriculum around this device. We need to give the teachers a box with all their experimental setting, with the lesson plans that they can really conduct that in their class. This is something that we are actively thinking of - how we can take this device and build some curriculum around it to introduce it to high school students.