Genes and evolution - from populations to tumours

Nell -  So this is about dogs and Epstein-Barr virus, which is type of virus that can cause some types of cancer.  And it can also do that in dogs as well.  And this could maybe mean that we've got a new model for studying this type of relationship in humans.

Kat -  Because there's quite a lot of human diseases that are actually in dogs.  I remember long time ago, there was a paper about I think narcolepsy in Dobermans and there were all these dogs just falling over asleep.  At the moment, there's no other animals that get Epstein-Barr virus.  Why do you think this is going to be useful?

Nell -  Well, one interesting thing about this virus and a lot of other types of viruses is that we know that many, many people are affected with them, infected with them rather.  But they don't always lead to particular types of cancer and everyone who's got the virus inside them.  So we need to figure out why that is, why some people are susceptible to this and others aren't. Perhaps we can figure this out in dogs.  It will give us some clues for what is going on in humans.  And that might lead to new ideas how to treat the disease or maybe prevent it.

Kat -  Because Epstein-Barr, this is really, really common particularly in places like Africa where it really causes a lot of cancers.

Nell -  Exactly.  So we don't really know what's going there, why are some people susceptible to this and others aren't.  We just don't know what's happening inside those cells in the moment.  And if we have an experimental model in dogs for example, that could really give us powerful idea to figure out what's happening.

Kat:: Another story that we also noticed this one is about the microbiome.  Now they've sequenced the human genome, they're trying to move on to sequencing all the bugs in our gut.  Is this possible now, do you reckon?

Nell::  It certainly looks like that.  I mean we've got so much more powerful genetic sequencing technology compared to, you know, 10 or even 2 or 3 three years ago.  And it's just really exciting the amount of data you can get out of this. And I supposed, the funny thing about this research is we don't really know what we're going to do with the data.  We've got this amazing potential for finding out all kinds of cool things but we don't know what those cool things are going to be.  So a lot of the coverage is a bit like as this hope, is it hype?  What are we going to do with that?  How is it going to help people? And we don't know yet but I don't think that's the reason why we shouldn't be doing it.  I think it looks really exciting and it could have a lot of interesting applications for a lot of kinds of diseases.

Kat::  Yes.  Some of the coverage I was seeing was saying, "Well we sequenced the human genome and you know, it hasn't solved everything."  But I don't think that's a reason not to do this because actually, when you think about it, manipulating the bugs in your gut is probably easy than trying to develop drugs to target gene faults.  Because have you seen the stuff about poo transplants?  This is great, we've seen this.

Nell::  It's really cool.  Yes.  That just sounds amazing.  So it's kind of taking all the bugs from someone else's gut and transplanting them into somebody who's maybe affected by autoimmune problems or they might have something wrong with their digestion.  And in some people it seems to have really amazing effect.  And again, you know, we don't really know what's going on there.  But if we can figure out how these little bugs are interacting, how they affect people, then we could maybe work out a nicer way to do that that doesn't involve transplanting poo.

Kat -  And speaking of sequencing and things like that, earlier in the program we heard from Mark Thomas, who's looking at human evolution and cultural evolution. And is there a nice story I noticed about cows. So what's going on here?

Nell - I really like this. So they were looking at DNA from ancient cow ancestral fossils from Iran, in fact. That's quite interesting because they've taken these bones from a very hot desert environment and still somehow managed to get DNA out they can use to figure out what the DNA sequences were back in those ancestors of cattle. And this kind of made people go, you know, "Ooh Jurassic Park, you know, we can recreate prehistoric cows". I got very excited. They're not quite there obviously. But it's interesting to see how you got this very small population of cattle that were initially domesticated and that has given rise to all the kinds of cows we have today. So it's quite cool.

Kat - Also it's cool in as well the point that they're making the, in the story also that these were Aurochs, big ox things. Now even when you start domesticating things like that, it's going to be tricky. So I think it's probably a number of years before they really got them domesticated. So, the early life of a cattle herder...

Nell - Yeah. It might have been more scary.

Scientists at UCLA have identified around 2,000 genes in zebrafinches linked to singing - more than 1,500 than were previously known about. All 2,000 show changes in activity levels when birds sing, and a number of them are also found in humans, making the researchers think they may also play a role in human speech and speech disorders such as autism.

Writing in the journal Nature Biotechnology, scientists in Australia have bred a new strain of salt-tolerant wheat, by crossing in a gene from a more ancient strain of the plant with a higher tolerance for salt. Around 20% of agricultural land around the world is affected by high saltiness, or salinity - which can seriously affect plant growth - and it's only getting worse as the climate changes. At the moment, the researchers have tested the gene in durum wheat, used to make pasta and couscous, and they hope to cross it into bread wheat next. Importantly, they didn't use GM techniques to get the gene into the wheat, so they're hoping this will speed up the process of testing and commercialisation.

Charles -  We have to determine how representative a single tumour biopsy was of the entire tumour genomic landscape.  And by that I mean if you identified mutation in one part of the tumour, how likely are you to identify that mutation in another part of the tumour?  Because clearly, if we're going to identify new ways of predicting drug response, we have to go for genetic events that are common throughout all parts of the tumour so that a random biopsy could pick those genetic events up.

And what we found actually is that, in the study when we took multiple biopsies from several primary renal cancers, and in some cases their metastatic sites, that the number of genomic aberrations or the pattern of genomic aberrations very often wasn't shared across all biopsies.  And in fact, when we counted the number of mutations, about two-thirds of the entire mutational load in the first two tumours as we sequenced were not shared across every biopsy taken from those two tumours.

Kat -  So this is quite a big difference from the original tumour.  You find differences in the gene faults within the tumour and also, in secondary cancers where it spread.  Presumably this almost blows personalized medicine out of the water, what do you think is going on here?

Charles -  No, I definitely don't think this blows personalized medicine out of the water.  I think what this does is actually begins to inform us that if we consider tumours as trees where we have the common mutations represent the trunks of the tree, these mutations are present at every site of the disease.  And the mutations that differ from one region to the next represent the branches.

Now, in terms of personalized medicine, one can perhaps think of HER2 or the BRAF mutation as the mutation or the amplification event that occurs at every sites of the disease and is therefore a good drug target.

Kat -  So that's the trunk?

Charles -  The trunk, exactly.  That controls the disease effectively because that mutation or genetic aberration is present at every site of the disease.

The model taken through is sort of logical conclusion also helps to perhaps think about how drug resistance is acquired, that low frequency events within the tumour that may confer drug resistance upon the tumour.  Our equivalent to the mutations perhaps that occur in the branches of this tumour to take the tree analogy further.  And during treatment, those resistance mutations may be selected out enabling the tumour to evade drug treatment.

Kat -  So when you cut off some branches it just keeps growing.

Charles -  Exactly.  That's right.  It's like cutting off some branches.

Kat -  What does this mean for the field of genomics research in cancer?

Charles -  First and foremost I think we need to sequence fewer tumours in greater depth and at multiple regions, comparing primary with multiple metastatic sites to really truly identify those driver trunkal mutations that are present and responsible for the disease biology at every site of the disease.  Those can be very efficient drug targets one would imagine.

It also tells us that actually understanding what's driving the diversity, in terms of the tree model, what's driving the changes between the trunk and the branches, actually maybe very important for trying to restrict underlying tumour diversity, to stop, if you like, the target from moving.  Because it's the diversity within the tumour that is likely responsible for tumour adaptation, resistance to treatment, and potentially the acquisition of mutations that allow tumours to grow at sites distant from the original tumour.

I hope in the next 10 to 15 years, considering tumours as trees, trunks and branches, it might help to improve the development and discovery of new drugs and enable us to understand how resistance to treatment is acquired by studying how these branches are cut off.

Kat -  You mentioned that you're sequencing the whole genomes of several samples of a single cancer, how have advances in technology allowed us to do this kind of research?

Charles -  I mean we wouldn't be able to do this research two or three years ago.  I mean the advances in sequencing machines, in computer technology, have been immense over the last two to three years and continue to be dramatic and will continue in the future to change and enable us to sequence tumours and process the data at an unprecendented rate

We're already seeing in some centres, in the US and elsewhere offer patients access to whole genome sequencing facilities as part of their treatment.  So already we're seeing human genomes sequencing impact upon patient care.

Kat -  And finally for you, where next for this research and for your team?

Charles -  What we're very excited about is the implications of this research to our understanding of how resistance is acquired during treatment.  Because it's only by understanding resistance to treatment that we will really make progress in prolonging patient benefit from the drug treatments we already have in the clinical setting.

So it's really understanding what's going on in branches of the tumours, it's understanding how the branches changed through therapy, and most importantly I think, understanding what initiates the change from the trunk to the branches, what is basically creating the underlying tumour diversity.

And when we've addressed to all of those problems, I think we'll have a much greater understanding of kidney cancer as a human disease and our, hopefully ability to target it much more effectively.

Most types of gene therapy are what's called somatic gene therapy - they're designed to only deliver genes to certain non-reproductive cells of the body, such as delivering a healthy version of the damaged cystic fibrosis gene only to the lung cells of someone with the disease. This is the main approach being used by scientists working in gene therapy. It's very unlikely that these genes could transfer into the sperm-producing cells in men, and even less likely they could get into the egg cells in women. Germline gene therapy, which changes the genes in sperm or eggs so they would be passed on to children, is actually banned in most parts of the world at the moment, for both technical and ethical reasons.