022 - Big Questions about the Big C

Kat: Hello, and welcome to Genetics Unzipped - the Genetics Society podcast with me, Dr Kat Arney. In this episode we’re digging into some of the mysteries around what’s often seen as the ultimate genetic disease, finding out how low doses of radiation might affect cancer risk and why tumours start in some tissues and not others.

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In many ways, cancer is the ultimate genetic disease. It starts when a cell picks up DNA faults that alter crucial genes that control cell growth and fate, ultimately meaning that it grows out of control to form a tumour. At least, that’s the official explanation. 

I’ve been spending the past year or so researching and writing a book about cancer that suggests the true story of what turns a damaged cell into and aggressive tumour - or a sad cell into a bad cell - is a lot more complicated.

This was neatly demonstrated by a recent paper published by Professor Phil Jones and his team at the Wellcome Sanger Institute in Cambridge, who have been looking at the impact of radiation on DNA damage and cell growth.

Large-scale nuclear reactor accidents like Chernobyl or Fukushima, or nuclear weapons like the the atomic bombs dropped on Hiroshima and Nagasaki by the US at the end of the Second World War, all release large amounts of X-ray radiation. 

First responders and people living nearby get a high dose of radiation, which we know can increase the risk of cancer by damaging DNA inside cells. So it’s understandable that the field of radiation safety focuses on reducing the risk of exposure to high levels of X-rays.

But many more people are exposed to much lower X-ray doses, either in the environment or through standard medical procedures such as CT scans, which don’t seem to have a noticeably damaging effect on DNA on cells growing in plastic Petri dishes the lab - at least, as far as anyone has been able to tell. 

So it may have seemed a little strange for EURATOM - the European Atomic Energy Community - to have funded Phil and his team to look at what, if any, are the impacts on such low radiation doses on health by moving from an artificial lab-based system to real life. 

But, as I discovered when I asked him to talk me through his study, the results came as a big surprise - with some big implications for our understanding of how cancer starts and grows.

Phil: We wanted to see what would happen not in dishes but in tissues, so we used transgenic mice where we can track the behaviour of single stem cells. We worked on the oesophagus - that's the tube that connects your mouth to your stomach - which is lined by some tissue. We looked at that oesophagus lining tissue.

We used a genetic cell tracking system to label cells and see what happened when we gave the animals a very low dose of radiation. This is about three or four CT scans' worth of radiation, a dose that has hardly any measurable effect on DNA at all. What we found is that this had a huge effect on normal cells' behaviour.

Kat: So, let's get this straight. You've got cells that you've already given them a head start, you've damaged a gene that is commonly damaged in cancer that makes them grow a bit more should they choose to. Then you give them a pulse of a low dose of radiation and then they start really going for it?

Phil: They really like it. Basically, they are in a competition with your normal cells and they are advantaged. The radiation, if you like, gives them a flying start so they are only running 80 metres, not 100 in the sprint and they get to the finish line first.

The proportion of those cells increases after a dose of radiation. If you give multiple low doses of radiation, it increases quite a lot. This is interesting because it might be a way that radiation would impact your future risk of getting cancer - still very low! - in a way that is independent of your DNA.

So maybe we need to rethink our understanding of how radiation might impact human health in the light of this. We've noticed this effect and it's got nothing to do with DNA directly, so why might that matter? Well, in other work that we've done we've shown that in normal people, in a normal human oesophagus, you start getting groups of cells which carry altered DNA. This is an inevitable result of getting older.

Kat: The hurly burly of life, your cells get a bit messed up as you get older, right?

Phil: Yeah. And these cells fight in a sort of Darwinian battle for space within the gullet. A few of those cells have altered DNA that makes them competent to grow a cancer.

Kat: So, just to get this straight, this low dose of radiation isn't causing new mutations, it's not piling more mutations on already mutated cells, it's doing something else?

Phil: It is doing something else and it's not, as far as we can say, acting directly on the DNA. It might have a very, very small effect but the cells are very good at detecting DNA damage and they don't notice that this dose of radiation has happened.

If you give a higher dose, a treatment dose of radiation, they do. But at this tiny dose the cells’ DNA damage response isn't even triggered. So what it is doing is affecting all the other bits of the cell other than the DNA and producing a lot of oxidative stress.

Kat: And what do we mean by oxidative stress? How does radiation cause this stress in cells? What is it actually doing at a molecular level?

Phil: Radiation splits up water molecules and generates very chemically reactive, very short-lived forms of oxygen, and that's what we call oxidative stress and those very --

Kat: Are these the free radicals?

Phil: These are called free radicals, which is nothing to do with far-left politics! It's actually about chemical reactions happening in cells. Then the cell needs to fix that damage and respond to it and that's the mechanism of action we're talking about here.

So if you like, we've moved away from thinking about DNA which is what we always focused on for a long time, to saying that you can change the ecology, if you like, the composition of the different species in the tissue in a less good way, by giving low doses of radiation.

Kat: People might have thought that you were a little bit crazy testing such low doses?

Phil: I agree. We had this research funding and I felt a bit sorry for the lead scientist on the paper, David Fernandez-Antoran, because I thought this project really won't work.

What was shocking and shocked us greatly was that actually, these very low doses of radiation have quite measurable, quite substantial effects on the behaviour of normal cells and on mutant cells. Because what they don't do is produce measurable changes in DNA damage, the sort of markers that the field has focused on for so long.

So it was a real shock to us that this worked. We were not expecting to find this.

Kat:  So, the dose of radiation that you're giving to these animals is very, very low. Can you put that in context with the kinds of medical procedures -- things like radiotherapy, x-rays or CT scans and then also the kinds of doses that you might get that we hear about when you're flying in an aeroplane or even living somewhere like Cornwall where there's quite a lot of background radon as well, that's radioactive in the granite.

Where do these doses sit in the grand scheme of things, from nuclear bomb to very background levels?

Phil: Well, a nuclear bomb is a bit extreme so let's not go there. Don't sit under a nuclear bomb is very strong advice.

Kat: Good advice, yes.

Phil: Levels of radiation that you get in say an aircraft journey are very, very tiny. It's very difficult to have any evidence of risks of those.

From medical imaging, having a normal x-ray like you would at the dentists or if you had a chest x-ray, that's still a very, very tiny dose. What I'm talking about and what we used here, is several body scans' worth. So we use this unit the milligray and it's 50 of those.

Most people will never have that sort of dose unless you need - and you'd only get given repeated CT scans if you have a very good medical reason to have them - please have the scans because the doctor prescribing the scans will have thought about the potential risks, which are very small - but it's that kind of level of dose.

Radon is different again because radon is a gas and it acts in a different way on tissues. I think we're looking at something that's above what having one scan would be, several scans. And I would put this as a theoretical risk, if you like, at the moment. I say theoretical, we don't know what the level of this is in humans.

Kat: One group of people who do have a lot of CT scans is cancer patients. Is there anything we can say about what those scans might be doing to the disease once it has already started and got going in their body?

Phil: I'm a clinician as well, I treat cancer patients, so what I would say is I and all my colleagues are ordering CT scans for cancer patients to help us decide the treatment. The risks of one or even ten CT scans causing any new trouble to your cancer or potentially giving you another cancer are so tiny they are very hard to even measure.

I'd really want to stress that. I don't want anyone to get freaked out and not have the imaging that they need to have. We don't do scans for fun, we do them to make a decision about somebody's treatment. Do we go on with this kind of therapy or do we give another therapy? Is it progressing, is it getting better? What's happening? So, nobody is getting a CT scan other than for a very good reason.

Where we do scans to monitor risks of people, for surveying people who might have a recurrence of cancer, again, we're doing that so we can step in early.

The levels of risk from the radiation in a scan are so tiny, they're so hard to measure that whilst I would never say to somebody who is completely well, have a scan as a health screening - I don't think that's a great idea - but if you have a cancer, the level of risk from the cancer is much higher than the level of risk from the scan. So to put it in context, that's how I'd view it.

Kat: I've been so used to, in my time writing about cancer, the idea that cancer is a disease that starts when one cell grows out of control and just keeps going and that's it - but this is a very new way of describing cancer as almost emerging from a battle within tissues. Of many things that could have had the potential, one ends up succeeding out of all them and it's more a disease of tissue rather than just one rogue cell really going for it.

Phil: The cancer that wins is a very rare single rogue cell that gets not one change in DNA, not two, but probably four or five. The chances of that happening are extremely low, which is why although we obviously all know a lot of people who have suffered from cancer or who are having cancer treatment, actually we have a trillion cells and we live for a long time.

So when you express it in terms of numbers of cells, that rogue cell is really extraordinarily rare.

Kat: I've been looking into the question of the interplay of genetics and cancer and tissue quite a lot for a book that I'm writing. There are so many people who are obsessed with the shopping list, almost, of mutations that you find in a cancer. Saying, “this must be important -  this must be what has turned this normal cell into a cancer cell.” And then the work of you and your colleagues here at the Sanger Institute showing that just normal tissue is a patchwork of mutations.

So this really tells us that we need to understand tissues a lot better and how our bodies work normally with this burden of general messed-upness.

Phil: I think that's right and I think that in the last few years, we at the Sanger but also other groups around the world have shown that humans really are carrying a lot of cells with all sorts of DNA in our normal tissues.

What that tells us is actually, although cancer is pretty common, one in three people will get a cancer at some point in their lives, actually, in terms of - when you look at it compared with that amount of altered DNA that we carry around in our cells, it appears really rare. Our tissues are very good at dealing with these mutant cells and keeping them in order and still working.

Kat: Presumably the model you have now of looking at these marked cells as they can expand or be snuffed out in the Darwinian battle, you could use that for testing other potential accelerators of cancer as well?

Phil: Absolutely and that's what we're doing at the moment. We're doing it for individual genes, which is what we did here and we're also using new DNA sequencing techniques so we can actually map the whole landscape of different clones fighting in this battle and see what happens when we give oxidative stress or an antioxidant or other stresses to this competitive balance.

Could it be that there are other things in the environment that trigger oxidation - in our diets, what we eat, what we drink, what we smoke particularly - that would also induce oxidative stress in those tissues and have a parallel effect, with radiation expanding the proportion of these cancer-capable cells? That's something that we are very actively researching at the moment.

So I wouldn't see low-dose radiation as being the sole focus of this work. It's really to say that the environment can change which species, if you like, in the Darwin analogy, thrive and survive. You change the environment; you change the nature of the beast that wins in that particular place.

If we can understand that, that will be critical for moving this towards something where we could help humans by tilting the scales in our favour.

We would not recommend anyone going and having low doses of radiation unless you need them for a medical imaging purpose. We certainly wouldn't recommend people taking antioxidants.

But I think what this says is that there might be, in the future, ways that we can modify our lifestyles, modify our diets, maybe take a short course of a tablet for a few weeks or months, that would cut our long-term risks of getting cancer. That's very exciting.

Very, very early stages, we're really just starting to work on this area of research but I think it could be possible that rather than just accepting that cancer risk inevitably goes up as we get older, that there might be interventions we can make to reduce it.

Kat: To get those unruly cells back under control?

Phil: Yes, exactly.

Kat: An optimistic idea from Phil Jones at the Wellcome Sanger Institute. Read more about his recent study and the scientific paper

Cells go to school

Kat: When we talk about cancer, we often talk about it as if it’s just one disease - the Big C. But its becoming increasingly clear that cancers can be very different depending on where in the body they start. 

Some are much more common - such as breast, bowel, lung and prostate cancers - while others, like cancer of the heart muscle, are vanishingly rare. The chances of successful treatment and survival also vary hugely, from 98% of men surviving testicular cancer for at least ten years to less than 1% surviving pancreatic cancer for a decade after diagnosis.

This issue of tissue specificity - where, why and how do tumours grow in different parts of the body - is one of the biggest questions in cancer right now. So it’s not surprising that it’s a question that the charity Cancer Research UK thought was worth millions of pounds, which they awarded to a team led by Steve Elledge, professor of genetics at Harvard Medical School, as part of their Grand Challenge award scheme. 

As you might expect, the roots of the problem go deep -  all the way back to the very earliest stages of life.

Steve: The big question in terms of which genes drives cancer and which tissues really has to do with development. That is, your body plan evolves from when you are an embryo, and in order to distinguish different tissues, they set up different sets of genes to control the identity and the evolution of those tissues.

So; a muscle develops in one way, a kidney develops another way and they're using different genes to be different and do their different functions.

Kat: And this goes deep because you start from one cell and then a little blob of cells and then you have to specialise into all these different tissues. That's a lot of decisions and a lot of genes, presumably?

Steve: That's correct. Development is a very complex process and people still don't completely understand it. But they understand the general outlines.

It involves a lot of cell identity and cell-cell contact and go and stop signals for when to divide. You don't want your leg to be too big, you want it to be just right. So signals to say grow, and signals to say stop.

Cancer is a rewiring of development. In order for cancer to evolve, it has to sort of undo part of the development of that tissue. Well, since that development is controlled by certain sets of genes, those genes differ in one tissue relative to another tissue.

So, altering a particular gene may have a profound effect in the tissue that uses it to maintain what we call homeostasis, which is the normal cell type, versus another cell type which doesn't really care about that gene because it doesn't use it.

So when you see the cancer grow up in say, your lung, there's a certain set of genes, a defined set of genes that it uses to maintain itself and those are the genes that are deregulated or mutated in cancer.

A different type of cancer, say bowel cancer, will be utilising a different set of genes. Sometimes they will overlap and sometimes they won't but it all depends on whether or not they reuse certain genes during their own development.

But they'll have a set of genes that they use to maintain homeostasis that if you altered them, will lead to uncontrolled proliferation.

Kat: So the way I like to think about this is that cells in your body, they kind of grow up almost like people do; they go through education, they go through training, maybe university or a course and they learn to do a job.

They've kind of picked up all these things along the way, they've made decisions to learn this and learn that. So the skills that a bowel cell needs is different from the skills that a lung cell needs.

So you're saying that if a cell says, "I don't want to do this job anymore, I'm going to do something else, do my own thing, become a cancer!" it still kind of knows where it came from, it still remembers its training programme?

Steve: That's a great analogy actually. You can also take that same idea, a person trained to do one job and you could even have it look a little bit like a computer trained to do a particular thing.

It has a programme that when you input some information into it, it processes that and something comes out the other end. Different cells have different circuitry, different programmes to them. So they take the same information and they can react very differently to it.

When you reprogram those, since each programme is different, you have to reprogram differently also, to get them to start doing other things that they're not supposed to do.

Kat: Taking this to its logical conclusion, when we talk about cancer as a general disease, is that really applicable if you start having to think about, OK, some cells in this particular tissue that have got this history, are doing this job and have developed a cancer and started going wrong, can we draw any similarities between that and other cancers in the rest of the body? Or do we actually need a different way of thinking about cancer, rather than just as one disease; as cells in a particular tissue that are going awry?

Steve: Well, it depends on what level you're looking at. If you come down from 30,000 metres, they all look very similar. When you get down to the ground level you start seeing that they are all very different. This is really the problem with cancer.

People say, "Why haven't you solved cancer?" Well, cancer isn't one thing, it's 200 different things. What works for one cancer doesn't work for another.

People are still trying to wrap their minds around this because some people work on a gene that is involved in cancers in multiple different cell types, but the solution to why it causes cancer might be different depending on that cell type.

Kat: You've just been awarded one of Cancer Research UK's Grand Challenge awards, to really nail down this issue of specificity; why do certain cancers arise in certain tissues? And how does their childhood as a cell, their developmental training, get involved there? Tell me a little bit more about the idea behind the project and what you're going to be doing?

Steve: Well, it all started with a very simple genetic screening we did on normal human cells. Most people, most cancer researchers, work on cancer cells.

Kat: Well duh, yeah, it's cancer.

Steve: Of course! But we didn't, we worked on normal cells because that's where cancer initiates. All the programming is intact in those cells.

So, we did a very simple screen where we turned on one at a time, each of 30,000 or so genes. We asked a very simple question: What makes you grow, and what makes you not grow if you make more of this protein?

What we found was that the things that made you not grow, there was a lot of commonality- it kind of made you sick. But the things that made you grow better were completely different. Only about 10% were in common between any two cell types. So that means that 90% is different.

Right away, we knew that this was really important in understanding cancer drivers. In our screening library of genes that we turned on and off, were many genes that were known to be involved in cancer. Many of them are tissue specific. When we turned them on in the right tissues, they did their job. They either made the cells grow fast, they made them grow slow, just like you'd predict from cancer genetics. They did nothing in the other cells.

Kat: So it really is about - you've got to have the right history in a cell, the right kind of training already there, so when you give it a hit with the gene that makes it grow, it's only going to be receptive to that signal if it's got the right history to it?

Steve: That's right, and it gets the same input and it does something different with it.

Kat: There's been an idea in recent years that you find a mutation in the tumour that is making it grow, and then you target it with a drug that blocks that, the faulty product of that gene.

Presumably then, cancers that have arisen in different tissues are maybe using these genes in different ways, that suggests that this kind of approach might work for cancers in some tissues, but maybe not for cancers in others?

Steve: That's actually correct.

Kat: Bummer. That is a bummer.

Steve: It is a bummer, but these are the targeted therapies and only about 20% of cancers even have a chance at a targeted therapy. Unfortunately, you can evolve around a single therapy rather easily.

That's why in the end we will need multiple different therapies that will be used at the same time. Sort of the way they've been able to handle HIV, with a triple cocktail of different drugs that work in completely different ways, so you can't escape them all at once.

It is true that these targeted therapies, they work really well with some cancers that have the gene that they inhibit, that we know is involved in the cancer, and not in others. We need to understand that.

Now, I wouldn't give up hope on those working in those other cancers, because they probably have some other circuitry that is somehow allowing them to get around it. If you can figure that out then it will really become a good therapy.

So I do think those will work. But it's definitely the case that everyone thought this is going to work for everything, but then by golly it didn't.

Sometimes they kind of work and then immediately you get resistance. Another aspect of cancer research is giving it early enough. So because it's a battle and if they have a big enough army of mutants, some of those mutants will be resistant. You'll wipe out 99.9% of the tumour and the .01% that's left will take over.

Kat: Steve Elledge, from Harvard Medical School. We’ll be returning to the challenge of combating the evolutionary power of cancer in a future episode, but you can read more about Steve’s Grand Challenge project on the Cancer Research UK Science Blog.

Third Time Lucky for Rats

And finally, the Faroe Islands form a rocky archipelago in the North Atlantic, famed as an ancient stronghold of those early invaders, the Vikings. But in more recent centuries the islands have themselves been repeatedly assaulted by one of the world’s most successful invaders: the brown rat. 

In this clip from the latest podcast from Heredity, the Genetics Society’s journal, James Burgon talks to Dr Emily Puckett from the University of Memphis about her latest paper looking at the history and population genetics of three waves of these furry Faroese invaders, from 18th century shipwrecks to the present day. 

Emily: So there is a shipwreck in 1768. It was a Norwegian ship that crashed off the coast of Scotland. The hypothesis and the historic record said that rats rafted on the ship wreckage all the way to Suðuroy. That's how they got to the Faroe Islands. And Suðuroy is the most Southern of the 17 islands within this archipelago.

Within two years, rats were seen on one of the larger islands, Streymoy, and then expanded to nearby islands Eysturoy and Vágar. It's really interesting that not all of the islands of the Faroes have been colonised by rats.

Additionally, this project had very clear hypotheses because of the historic record, about both the source populations of the invasions as well as the timing of the invasions. We really wanted to test both of those pieces of each hypothesis.

On a bigger picture perspective, we're really asking; how well do historic records of invasions match what we can learn from population genomics?

This project is particularly interesting because it really tests the limits of population genomics to understand this type of demography because the invasions of the Faroes were so recent in time.

Kat: You can hear the full interview in the latest Heredity podcast - just search for Heredity in your favourite podcast app.

Paper: Genomic analyses reveal three independent introductions of the invasive brown rat (Rattus norvegicus) to the Faroe Islands https://www.nature.com/articles/s41437-019-0255-6

That’s all for now. Next time we’ll be back with more stories from our series exploring 100 ideas in genetics.

You can find us on Twitter @geneticsunzip or email us at podcast@geneticsunzipped.com with any questions and feedback. Please do take a minute to subscribe on Apple Podcasts, or wherever you get your podcasts from, and it would be great if you could rate and review - and more importantly, please spread the word so more people can discover the show.

Genetics Unzipped is presented by me, Kat Arney, and produced by First Create the Media for the Genetics Society - one of the oldest learned societies in the world dedicated to supporting and promoting the research, teaching and application of genetics. You can find out more and apply to join at genetics.org.uk  Our theme music was composed by Dan Pollard, and the logo was designed by James Mayall, transcription is by Viv Andrews and production was by Hannah Varrall. Thanks for listening, and until next time, goodbye. 

Image: Skin cancer cells - Squamous cell carcinoma, NIH Image Gallery via Flickr Attribution-NonCommercial 2.0 Generic (CC BY-NC 2.0)