Robyn Williams: Why would a top cancer specialist in America call an astrophysicist for advice on how to tackle one of our biggest killers? What could a knowledge of outer space and cosmology offer doctors about treatment? It's a fascinating story.

Paul Davies was at the University of Adelaide. Now he heads a team studying origins at the State University of Arizona. This week he appeared at the Lorne Cancer Conference in Victoria to talk about his work. But the lecture you are about to hear comes from the Adelaide Festival of Ideas.

Paul Davies: Good afternoon ladies and gentlemen, it's a pleasure to be back here at the University of Adelaide where I worked for about 10 years in the 1990s. And as Robyn has indicated, I'm going to be talking about something completely different. For those of you who have followed aspects of my career you'll know that primarily I'm a theoretical physicist and cosmologist and have turned in more recent years to the subject of astrobiology. What's that? It means searching for life elsewhere in the universe and trying to understand how life got going here on Earth.

I'm going to tell you the story in a moment about how I came to be caught up in cancer research. I should say right at the outset that cancer touches every family on the planet. It's one of the most intensively studied phenomena in biology, and yet it's one of the least well understood. And so my title 'What is cancer and how can we manage it?' is very well chosen, because in spite of the many, many years and thousands of researchers and millions of published research papers, there is no consensus on what this phenomenon we call cancer actually is. And the word 'manage' is also very carefully chosen.

But let me first start with a bit of history. Back in 1971, so more than 40 years ago, President Richard Nixon declared war on cancer. I'm told he never actually used that terminology, but it's a metaphor that has persisted. People always talk about battling with cancer and the war on cancer. And so we've had more than 40 years and the question is, how are we getting on?

Well, first of all let me turn to the financial aspect. The cost of cancer research is really quite staggering. The United States spends $5 billion a year of taxpayer money, and then there's charitable money on top of that. Just to put that into perspective, that's more than the US government spends on space exploration. So people who say we are wasting all this money on space and we should be spending it on cancer research, it's a comparable figure. And the total price-tag over the duration of the war on cancer is about $100 billion. This is just US. There will be comparable figures, say, for Europe and other parts of the world.

The costs of cancer are not just in the research but cancer healthcare. Healthcare figures are very hard to interpret because they include all sorts of hidden costs, so I don't propose to do that, though I saw the figure of €162 billion per year for Europe as the cost of cancer care and cancer management. But the one thing it's easy to put a price-tag on is the cost of cancer drugs. And so a course of anti-cancer drugs might typically be around US$100,000, and it's very easy to see that as people live longer, more people get cancer, cancer incidence is rising remorselessly, that the cost of treatment, just drugs alone, is set to bankrupt the US economy. So this, just in economic terms, is really stupendous.

Now, you might be wondering, what are we getting for all this money? Well, here are some chilling statistics. Death rates in the United States…and what it's doing is comparing some major killer diseases like heart disease, pneumonia and influenza for example, all of which…between 1950 and 2004 all of which have come down really quite dramatically. So infectious diseases, we're on top of those. Of course they are not eliminated, but huge progress. And when Nixon signed that law back in 1971 he said, 'We will conquer cancer in five years.' So the expectation was that this will be the next thing to fall to the miracles of modern medical research. But look at what has actually happened; a slight improvement but overall nothing very dramatic at all.

There are lots of ways you can calculate these figures. People will talk about death rates, they'll talk about survival rates, whichever way you look at it the figures are overall gloomy. That conceals the fact that there are some limited successes in extending life expectancy, and in the case of childhood leukaemia quite spectacular advances. Some cancers are killing less people now, some are killing more people. So it all pretty much averages out. There has been progress but it's very slow, in fact painfully slow.

And so when you find something so intensively studied as cancer over such a long period of time with such huge resources poured into it and very little progress, it makes you wonder if perhaps progress is slow because we are thinking about the problem the wrong way. In other words, instead of saying we are not spending enough money, we can solve this problem if we throw enough money at it, maybe we are not thinking right. Maybe it's not a question of money, it's a question of rethinking the problem from the ground up.

And the reason that I came to be involved is entirely due to a phone call from this lady here, Anna Barker. At the time she was deputy director of the National Cancer Institute. It was a phone call out of the blue, she said, 'You don't know me but I've noticed the centre that you've established at Arizona State University, the Beyond Centre for Fundamental Concepts in Science…' where you consider foundational questions across all the sciences, you go right back to basics and ask what are the hidden assumptions we are making, how can we reconceptualise this problem, how can we make progress. And she said, 'You physicists seem to be really good at solving problems because you can figure out what's going on inside atoms, you know what's happening with the age of the universe, you've got all this clever stuff; can you help with cancer?'

Well, what was I to say? Sure, we can help out. But I said, 'But unfortunately I think you're talking to the wrong person, I know nothing about cancer.' And she said, 'That's perfect.' And that's how it all began. I should mention as a postscript that this lady is now working as a colleague of mine at Arizona State University, she is now one of my colleagues. So this is a story that she likes to tell and I like to tell and we seem to have the same version of it.

So I came into it cold. And the whole idea was to bring a fresh perspective to a very deep and complex set of problems, and she asked me to give the keynote opening address at the initial pre-cursory workshop, and I just sort of reeled off a few things. But what I said was that one reason to bring in physicists into this field is that they can ask really stupid questions, seemingly without embarrassment. And sometimes those really stupid questions like, 'Explain to me how that works,' and, 'Supposing you ran it backwards,' and, 'Would it matter if you turned the temperature up a bit,' all these sorts of questions cancer biologists often say, 'Oh, well, nobody has ever asked that,' or, 'That's a very good question,' or, mostly, 'Well, nobody knows.'

And I always figure if you get a lot of clever people in a room, the sum total of what everybody doesn't know is what is really interesting because that's where progress is likely to be made. That is the opposite of brainstorming, you get people together and you say, 'Let's pool our knowledge.' Well, I'm after pulling ignorance because it's in the gaps of ignorance that we are likely to make progress.

Anyway, the upshot was that the National Cancer Institute, in an extraordinary farsighted and generous move, decided to create 12 centres for physical science and oncology, this ungainly acronym, PSOC, scattered around the country, and that's us. And it won't surprise you to learn that I'm running the show at ASU. And the whole plan is that each of these centres has a physical scientist, not necessarily a physicist, it might be an engineer, nanotechnologist, chemist, but a physical scientist twinned with either a cancer biologist or an oncologist. So we really make an effort to talk to each other.

We work in collaboration with the Mayo Clinic in Scottsdale and the Fred Hutchinson Cancer Research Centre in Seattle. And so the lineup of talent here is that we've got six clinical oncologists or cancer biologists, five physicists, a physical chemist, an astrobiologist, three engineers or nanotechnologists, one education outreach person, and we have about 15 mainly graduate students working in this.

So let me come on to what my own contribution is, apart from administering this monster. My advice to anybody here is never deal with the US government. The troubles of the last couple of weeks are only minor in comparison with all the things we have to put up with in terms of reporting and accounting and never knowing what our budget is. It's a real challenge just to do that.

I've also never run an interdisciplinary research group, it's like herding cats, and so it's a challenge both looking up to Washington and looking down to my colleagues and particularly with their lab work because I'm a theoretical physicist, so for me all my work is up here but for them it's in test tubes and they don't let me in near them, and if I go into the lab I have to promise not to touch anything. But I'm sort of responsible for the whole show.

But in addition to running it I've tried to make a real contribution to this subject by doing what I think all good physicists should do when they're faced with a really knotty problem is you go right back to basics, you ask the most fundamental questions of all and then you try to build up a conceptual framework. There is no way I can compete with mainstream cancer researchers on their home turf, that would be ridiculous. The best I can do is bring a lifetime of experience across several sciences and survey the scientific landscape and spot what I think are significant facts, almost all of which will be known to somebody in the cancer community, and connect the dots in perhaps a novel way. So I'm trying to change the culture of thinking, the culture of research in cancer biology. So it's a matter really of affecting a change in thinking.

And so I've tried to develop a theory of cancer in the sense of you might think after all this time there would be a well-defined theory of cancer, that we would understand what it is. Not at all. And so I think we have to position cancer in the great sweep of the story of life on Earth. So here it is, the questions; what is cancer? Most people take it for granted, well, it's a disease to be cured. What is cancer? Why does it exist in the first place, and how does it fit into the great story of life?

The take-home message is one that is both good news and bad news. I don't think cancer is a disease to be cured, I think it's a condition or a phenomenon to be managed. I think we can manage it, but the lure of the cure I think has distracted a lot of research. People want a pill to make it go away. I don't think there will ever be a general purpose pill to do that. Cancer is not that sort of thing, it's not like an infectious disease.

So I often say cancer is a bit like ageing. I go around the world, and everywhere I go there is ageing, I see it everywhere, people are dying of it in every country I've visited, there seems to be nothing we can do to hold it back. Of course we can't stop ageing but we can mitigate its effects, we can have huge effect on quality of life and life extension, and this has happened in Australia and elsewhere. And cancer is the same. It's not something that we should really think about curing, we should think about preventing it and managing it, and I think we could do a lot better at the management than we do at the moment.

What is cancer? It's a very simple story. People say it's a complex disease, but actually it's a very predictable disease. What happens is cells start to proliferate uncontrollably in a particular organ, and then they spread around the body, that's called metastasis, colonise other organs, and the outcome is usually bad. The 90% of fatalities from cancer are not caused by the primary tumour but by this dissemination. And you might think that seeing as that's so familiar, millions and millions of people every year are diagnosed with cancer and it follows this pattern, you might think physicians would have a pretty good idea of what's going on, but they really don't. So a lot of details, a lot of facts, but no real understanding of what this phenomenon is and why it exists.

So a primary tumour in a particular organ, there's a cascade of events, all of which requires cancer cells to acquire various functions that they didn't have at the outset. Gain of function and loss of function are an important part of the cancer story. So the cells transform as they go through this journey because what happens is the cells will leave the primary tumour, often in procession, get into the bloodstream, spread around in this raging torrent, get out of the bloodstream, enter a remote organ and make a home there, colonise it. There are many steps in that process.

The thinking behind bringing physical scientists in is that in addition to cancer cells responding to various sorts of chemical signals and various types of genetic information processing, they are also physical objects, they are little things with physical properties, like a size, a shape, they undergo shear stresses and they have elastic properties, all sorts of physical things have to happen to cancer cells and will change with cancer cells. If we understood those physical changes, it gives us a handle to control them. There are even electrical changes. I'll touch on that very briefly later.

Let me take some significant facts, often overlooked. Cancer doesn't actually invent anything new. All it does is accesses or appropriates existing modalities, that is biological function which is already there in the organism, but it's deployed in an abnormal way. A lot of people think that cancers are like rogue cells running amok, but it's more organised than that. It's almost like a loosely cooperative multicellular organism, and I'll come back to that because it's part of what I'm trying to develop in the theory.

Cancer is characterised by a number of hallmarks, one is its proliferative ability, I've already said that, it multiplies uncontrollably. The other is its ability to evade programmed cell death. Multicellular organisms are based on a contract that was signed about 1.5 billion years ago between individual cells in which the immortality of the unicellular world where the only imperative is replicate, replicate, replicate, was subordinated to the agenda of the collective. And so in a multicellular organism, most cells eventually die. Most cells are called somatic cells—skin cells and kidney and liver and so on—they get a certain number of replication events and then they die. It's programmed cell death. And that trade-off, well, the germ line, the germ cells, the eggs and sperm carry the immortality into the next generation, and the cells of our body have outsourced that function to these sex cells they carry into the next generation, and they pay the price by undergoing this process called apoptosis or programmed cell death. Cancer disables the apoptotic pathways, and a number of other things as well. But the point I want to try and get across is that these functions of cancer cells are co-present in the same population of cells, sometimes in the same cells.

And when I first learnt about this I thought, well, everything you're told about cancer is that something has gone wrong. It seems to me that the best way of thinking about it is really not so much that these are cells that have gone wrong but cells that are doing something very efficient. They are going right as far as their agenda is concerned, they're very good at what they do. In other words, instead of thinking of cancer as an aberration, I rather prefer to think of it as unleashing a potential which is there all the time, a modality that I'm daring enough to call pre-programmed. And this raises the hackles of a lot of cancer researchers. But I think the cancer occurs because the suite of modalities which cancer needs to fulfil its agenda is pre-programmed into pretty much all the cells in your body at the outset.

Robyn Williams: And you're listening to The Science Show on RN with Paul Davies at the Adelaide Festival of Ideas, talking about physics and cancer.

Paul Davies: The standard theory of cancer is that it results from the accumulation of genetic damage, maybe from radiation or carcinogens or just ageing, just defects in the replicated machinery, and this accumulates over a period of time and then reaches a sort of threshold at which the cell then goes berserk. But the important point is that cancer isn't something…apart from the Tasmanian devil, isn't something you catch, it's something that develops de novo inside your body. So it's reinvented from the bottom up each time, and that's the standard theory. I've got to criticise that. So the standard theory is the cancerous cell has gone wrong but gone wrong in the same way in all individuals and in other species as well, whereas the theory that I'm trying to develop…and I neglected to say right at the outset that everything that I'm talking about is developed in collaboration with Charley Lineweaver at the Australian National University. Charley like me is a cosmologist and theoretical physicist with an interest in astrobiology and now turned into amateur cancer researcher, and we've been collaborating on this together with some postdocs and students at Arizona State University.

So the theory that we are proposing is that cancer is actually a pre-programmed ancient like subroutine, if you'll permit me to use this computer analogy, a subroutine that is preloaded into cells and genomic accidents may trigger the cancer subroutine but they are not primarily the cause of it. In other words, it's an accident waiting to happen. There is certainly genomic instability in cancer. If you sequence cancer cells, they are very heterogeneous genomically, they have accumulated lots of mutations, but the assumption is usually that the mutations are causing the cancer. We think the cancer is a response to a stressful environment and that the mutations are largely collateral damage. That is, they are incidental to the cancer story. It's the cancer that causes the mutations, not the other way around. That's the theory anyway.

The standard theory, called the somatic mutation theory, I've called it dogma to be provocative, is a bottom-up theory; something goes wrong at the molecular level, at the DNA level, genetic accidents accumulate, they give rise to cancer, and that destabilises the cells and there are further mutations and it becomes…I was going to say a virtuous circle but whatever the opposite of that is, an un-virtuous circle. So we think that that is probably not the way to think about it. We have a sort of top-down theory that we think that cancer is a response to a stressed environment. I must say at the outset when I use that were 'stressed' everybody thinks, oh yes, I'm always rushing around, I feel stressed, I'm going to get cancer. It's not the way that scientists mean when they use the word 'stressed'. A stressed environment or a bad environment might be one in which pressure is elevated or the pH has changed or there may be a drop in oxygen tension. So what I mean is biologically stressed, not psychologically stressed. And that that is leading to the cancer, and the mutations are part of the cancer phenotype. The genotype is the genetic information, the phenotype is its expression in the actual physical organism.

So I said that I have an analogy; think of cancer as like a genie in a bottle, an accident waiting to happen, all cells have the potential to become cancer cells but they are sitting in there and mostly they don't cause any trouble. And I have to say that even when they cross the line and become cancer cells, in a healthy tissue environment they are restrained. In other words, there are many regulatory mechanisms which in a healthy organism prevent tumours from forming. But a variety of things can let the genie out of the bottle, and then when the genie has escaped we are claiming that that genie executes the program or the subroutine with rather ruthless efficiency. So the genie is not something gone wrong, the genie is a breakdown of the regulatory apparatus that prevents the genie from enacting its program.

In a nutshell what I think is not wrong but a distraction of modern cancer research is there's a huge amount of effort and money being spent picking over the shapes of the shards of glass that have released the genie in the hope that elusive patterns will emerge, and people will say, ah, we've noticed that in this cancer this edge and that edge has got a certain angle and so on. Of course I'm using a metaphor, but the point is though that they're looking for clues in the damage, in the shattered regulatory apparatus that has released the real culprit which is the genie. So I think they are concentrating on the wrong target. There are many ways you can shatter a bottle, many ways of letting the genie out, but once the genie is out, its own performance will be really rather predictable.

It's a striking fact that if you take a cancer cell and put it in a normal tissue environment, it usually doesn't progress. In other words, the micro environment of the cell acts to control the destiny of that cell. You can really take quite grotesque cancer cells, that is very badly distorted cells, both genetically and physically distorted cells, and they will still behave more or less normally, they won't cause trouble anyway in a normal tissue environment. If you put enough of them together, however, they sort of take over, and then they appropriate or recruit the healthy cells in their vicinity. So really it's a case of if you can't beat em, join em.

And I sometimes (it goes down well in America) say, well, it's a little bit like the early European settlers, they came over in their boats and then they built forts on the east coast of the United States and they had a rough time and they kept their heads down and they were confined, and then they bribed a few of the local Indians, recruited them to the cause and then they reached a sort of critical mass and then they burst out and took over the country. Well, it's a little bit like that, that cancer will spread around the body, will colonise these organs, but very often these micro tumours make little progress and they just remain dormant, sometimes for years, sometimes forever.

And so this makes for a confused picture because it's wrong to think that people either have cancer or don't have cancer. It's not like, well, you know, I've caught the flu or I haven't caught the flu, it's not one of those open and shut things. As the body ages, all sorts of cells undergo all sorts of changes down this pathway, and the vast majority of these cells never present clinical symptoms. And so what we would like to understand is under what circumstances do they become problematic, and can we then manipulate the physical parameters…that's my dream is a physicist, manipulate the physical parameters to prevent that dissemination spread and explosion out of the niche that they've colonised.

Now, I say 'physical spread' because the way in which cancer is treated at the moment is largely by surgery and drugs, and the drugs are really a chemical attack on those cells, whereas I have this idea that we need to look to the physical environment. What is that? I've already mentioned it could be things like temperature, oxygen tension, pressure, shear stresses, electric fields, there's a handful of these things and these parameters matter.

For example, we have an interesting lady who works at Arizona State University, Cheryl Nickerson, and NASA pays her to send salmonella into orbit. And you might think, well, why are they doing that? As you probably know, for every…I think we've got about 100 billion cells in our body, but we have a trillion parasites, often called the microbiome or the microflora or microbiota which are an essential part of healthy living. So our guts are full of bacteria and archaea, our skin, our lungs, they are crawling all over us, it's a yucky thought, but they really fulfil an important function.

And so the point is, so if you go into orbit, say with some salmonella in your gut, could it be that you don't fare so well in zero G than you would down here on the ground? And sure enough the gene expression of these microorganisms will change in a low gravity environment. So in other words, bacteria have the ability to be able to sense the physical forces in their micro environment. Sometimes this is a phenomenon called mechanotransduction. Mechanical forces can be transduced into changes in gene expression. So the way in which a cell or even an organism behaves, its phenotype, its gene expression, can depend on the physical forces acting in its environment. It's one example, it's a very striking one.

Here's another one that I really like, the work of Michael Levin at Tufts University, he measures the electric fields inside cells. He likes particularly these little worms called planaria and he does these diabolical experiments with these worms. These are favourites among schoolchildren because you can chop them up and they regenerate. So if you chop a planarian in two, the head grows a tail, the tail grows a head and you've got two of them, and that's great fun. But it turns out that they have an electric polarity, both within the organism as a whole and within cells. So the secret electric life of cells is a really fascinating subject that has not really been much studied. But with various clever dyes you can actually measure electric fields in and around cells.

When you have a wound there are electric fields around that wound. If you have a limb regeneration, for example in salamanders, there's a whole electric story going on. So electric fields are part of what biologists call morphogens, but they're normally thinking of chemicals, but electric fields also play a role in helping shape the phenotype. And the extraordinary thing is that if you manipulate these electric fields, what you can do is you can grow two-headed planaria and two-tailed planaria, and I find it endlessly fascinating that when I asked Michael Levin were these ones really stupid compared to those, he said, well no, it didn't seem to make too much different. But the key point is they all have the same DNA, you see. But clearly their phenotypes are different, so the gene expression has depended on, in this case, their electrical circumstances.

So if we are right then, that there is a cancer subroutine lurking inside all cells, if cells come preloaded with it, why is that? Why hasn't evolution eliminated it? And the famous dictum of Dobzhansky, that nothing in biology makes sense except in the light of evolution, is our guide here because Charley and I thought, well, what is going on here with this cancer stuff, how can we make sense of it?

And the first thing we noted was the fact that of course cancer is not restricted to human beings, it's pretty much pervasive across the multicellular world, all mammals, fish, with the exception of the naked mole rat, but I'm not going to get into that…all mammals, fish, birds, reptiles, and even plants have cancer or cancer-like phenomena. So this is obviously something that is deeply rooted in the evolutionary sense. It will go back at least to the point of common ancestry of these organisms, and that's hundreds of millions of years. But we think because cancer has to do with multicellularity, we think it goes back to the dawn of multicellularity which was about 1.5 billion years ago.

I've already said unicellular life just wants to replicate, multicellular life is a contract outsourcing the immortality to the germ cells, apoptosis is the price that the somatic cells pay, and cancer is a breakdown of that contract. Somatic cells, like a liver cell or a lung cell, say no, I'm opting out, I'm going to do my own thing, I'm going to make a bid for immortality and to hell with that contract. And all of the policing, all the regulatory mechanisms are ignored or evaded or disabled, apoptosis is switched off, various other mechanisms, all at once, all those modalities are either disabled or other modalities are switched on. And so it's a very clever and systematic response, it's a breakdown of their contract.

I first got to think about this because of reading this paper in Nature about three years ago about the sequencing of the genome of a sponge, actually an Australian sponge found in Queensland, which has identifiable tumour suppressor genes. So even a sponge, even something that primitive needs to worry about cancer. It has a lineage going back about 600 million years, so you have to go back a long way before humans and sponges intersect, but nevertheless cancer is a problem going all the way back.

You might think, well, evolution has had then hundreds of millions, if not longer, of years to get rid of cancer because it was killing organisms. Why have we still got it? Why is it still around? And the answer, as always in biology, is it's a trade-off. If something that is bad for you is still there in spite of evolution, it must mean that it is also fulfilling a useful function. What is the useful function of cancer? The answer is embryogenesis. The development of the embryo involves the up-regulation or the expression of key genes which are reawakened in cancer. I should say just in passing, it's not just embryogenesis, wound healing and the immune system are also aspects or modalities that the cancer is appropriating in an inappropriate context. In other words, cancer is using things that healthy organisms need, like developing embryos, wound healing and the immune system, and it's using them for its own purposes.

This has been known for many years. There's this paper from 1987, 'Oncogenes and Development'. Oncogenes are genes which are implicated in cancer, there's a long list of them, and these genes are active in embryogenesis. The work of Isaac Kohane at Harvard MIT, a very good article in Scientific American, he is quite explicit that he has identified genes that are up-regulated, switched on, in most cancers and these are genes which are active in early development.

So there's really no mystery about this, but when I discuss it with my oncology colleagues and my cancer biology colleagues they'll say, 'Well, yes, I think we know that, so what, what's new?' What's new I think is that it is clearly a deeply significant clue to about how cancer comes to exist and what it is, the fact that it is reawakening genes which are active in early-stage embryogenesis and normally silent thereafter. So it's just a question of not damaging the genes but switching back on genes that should be left silent.

Genetic damage can lead to that. So in other words if a tumour suppressor gene or a revelatory mechanism is arbitrarily damaged, just smashed in some way, then it may simply release the potential for the genie to do its stuff, in this case expressing genes which should remain silent except during embryogenesis. So it could have a trigger, it could be a mutational trigger, but the actual deployment of those modalities is something which is very systematic, very organised, and really quite frightening in terms of its efficiency.

So our hypothesis then is that cells become deregulated, for one reason or another, due to stress or accident, and they are defaulting back to an ancestral pathway. And the reason I say ancestral is because the basic body plans of human beings are pretty much the same as the basic body plans of dogs or fish, you can look at the early-stage embryo and they all look more or less the same in the early stages and then the differences develop later. So the very early part of embryo development recapitulates the common origin of these multicellular organisms. So these are, so to speak, the ancient genes.

I always get ticked off by my biology colleagues that all genes are ancient, you know, they've all come from somewhere, whether a trail that goes back 3.5 billion years, but in some sense some genes are widespread and conserved and have remained largely unchanged for hundreds of millions of years. We're calling those the ancient genes or the old genes. And the genes that lay down the basic body plan had better be like that. So the ancient genes are also the ones that are active in early-stage embryogenesis. So this is we like to say an atavistic theory of cancer or a throwback theory of cancer. We're saying that cancer is recapitulating not only early multicellular life but early embryogenesis as well.

We go beyond that…so no point having a theory if it can't be tested. We think that as cancer progresses, say from the first glimmerings of dysplasia in a cell of changes, right up to the full-blown disseminated malignant metastatic disease, that it's like running the arrow of evolutionary time backwards at high speed. And here we see three arrows of time, we see the evolutionary arrow of hundreds of millions or billions of years, then there's the developmental arrow, the ontogeny arrow over nine months, in the case of humans. And then we have the carcinogenesis arrow runs the other way over a period of weeks, months, maybe a few years. So it's like running that backwards. So that's a very specific prediction and we're trying to tested by looking at phylogenetic data across many species, trying to date the genes and look at the genes which are active and implicated in cancer to see if these are really the ancient genes, and also to test, as cancer progresses, whether there is a change in the depth on the phylogenetic tree of the genes that are causing the problems.

I mentioned atavisms. You may know an atavism is when an organism is born with some sort of ancestral trait. In the case of the dolphin, four fins instead of two. There are many known examples of this even with humans, humans born with tails for example. This sort of thing can happen, and it gives a clue because what it means is that in spite of the fact we've divested ourselves of those features, maybe tens of millions of years ago the information to create them is still in our genomes, it's just that the pathways to switch them on are hidden and normally silenced. So in other words we have a lot of atavistic features already. It's well known in biology, atavistic features can be retained, they'll be retained for a function, you can be sure, and we think cancer is a very ancient type of atavism in that sense.

Another analogy I like to use is a computer that starts up in safe mode. So if you drop your computer you see this horrible screen and you think, oh dear, I've got trouble now. Or it may be a software glitch, you've loaded some latest version of something, Java or something, and it all goes wrong and you get safe mode. Safe mode is simply a way of running the core functionality of a computer with a limited set of capabilities, and it's enough to keep the thing going. I see cancer as a bit like that. Cancer, by being a throwback, is divesting itself of a lot of modern functionality which is unnecessary to run the core functionality, the inner core. The genie is that inner core of largely undamaged genes and regulatory pathways. It's not just a package of genes, it's more complicated than that, but it's a core functionality which it runs. And the reason that you see all of this mutational damage is because the genes that mutate are simply abandoned because there's no point in expending resources in all the editing and error correction functions for those genes that are not part of their core functionality. So there's another metaphor.

So what I've done (I want to pull this to a conclusion) is build bridges between cancer biology, developmental biology and evolutionary biology and astrobiology, as Robyn mentioned, an important part. These are subject areas where people don't normally talk to each other. What we do at Arizona State University is we bring them together. We have brainstorming workshops where we mix up people from these different disciplines and try to drill right down to the fundamentals so we can come to understand cancer in new ways. We have an undergraduate called Adam, appropriately enough, who is going back on the phylogenetic tree and he has trod those vast databases across species and he's trying to make sense of the cancer database and he is doing great work trying to correlate these two, but it's work in progress.

Can I mentioned one thing which is the work of Otto Warburg who back in the 1920s thought that cancer was less to do with genes and more to do with metabolism, the way in which cells utilise for example sugar and how they use oxygen to produce energy. I'm not going to go into the details, partly because I don't understand the details, but he felt that some sort of error or dysregulation of this type of respiration was the main hallmark of cancer, and it's certainly the case that if healthy and cancer cells are subjected to a reduced oxygen environment, hypoxic is the term, a hypoxic environment, they can do metabolism another way, they can do something called the fermentation or glycolysis and they make their energy that way. Cancer cells prefer that way of doing it, whereas healthy cells, once you restore the oxygen they go back to the oxygenic method.

So we feel that…a prediction of our theory that we think that if cancer is a throwback to an earlier form of life, its most comfortable environment is an early environment. And when you look back at the oxygen levels on Earth, it underwent two great surges. One was about 2 billion years ago, the first great oxygenation event. And the next one was about between 600 million and 800 million years ago. And multicellularity evolved in that plateau in between when oxygen levels were much less than they are now. In other words, multicellular life dates back from a hypoxic world. Embryos are hypoxic, tumours are hypoxic, and we think there is clearly a clue in that.

What are we going to do in terms of treatment? It's all very well having a theory but does it make a difference in the clinic? We think so. There is a general principle which is that when you deal with something as efficient as cancer it pays not to target the strengths because it usually wins in the end. For example, one strength is proliferative ability, and most cancer drugs target that proliferative ability, but the cancer usually wins. We think we should target the weaknesses because we think that gains of function are really regaining deep, ancient and therefore very well protected functions. Proliferative ability is the default state of cells. You go for that, you're going for something that has been around for 3.5 billion years, life has learned a lot of tricks in that time about how to evade threats.

On the other hand, cancer can't have it both ways. If it's a reversion to an earlier or ancestral phenotype, then it's going to divest itself of some modern functionality. For example, I've mentioned oxygen. It's going to be uncomfortable in a normal oxygen environment. So what you need to do to control cancer, not cure it, not even eliminate it but just control it, slow it down, is create an environment that targets the weaknesses of cancer that makes the cancer cells feel more uncomfortable than the healthy cells.

In practice, though this is just one example, one way of doing this…I mentioned about the oxygen story, hyperbaric oxygen therapy is one way of flooding the tissues with oxygen. Glucose restriction. Cancer loves sugar, hates oxygen, so you give it lots of oxygen and very little sugar, and that might mean starvation or at least dietary restriction, and the pH, we don't need to worry about that here.

So that is one way of proceeding. A paper just out last month, the ketogenic diet which is basically a low sugar diet and hyperbaric oxygen therapy prolonged survival in mice. There's an awful lot of dead mice out there I have to say in the history of cancer research, and of course just because it works in mice doesn't mean it will work in humans. But we are having a workshop next month with the leading advocates of people who think cancer is a metabolic disease, just like Otto Warburg suggested decades ago, we'll see what clinical evidence they have to present, that this could be a therapeutic advantage. The great advantage of this, which is basically 'turn up the oxygen, change the diet' is you don't need clinical trials, people use hyperbaric oxygen therapy for all sorts of other reasons, so you don't have to go through this long expensive business as you do with drugs that take decades, cost hundreds of millions of dollars and mostly don't work when you've finished. So using physical means to control cancer is going to translate into much more rapid clinical advantage.

I want to end by being even more provocative because there's one other aspect I want to mention here. You'll probably get up and walk out at this stage! But one of the so-called modern functionalities that organisms have, like us, is an adaptive immune system. It's very clever, it works very well, so if we get a germ inside us it gets attacked by the immune system which can adapt and zap it. But, if we are right, cancer is a reversion. The adaptive immune system evolved about 400 million years ago, and so advanced cancer should decouple from that adaptive immune system. That's our prediction, it would decouple from it. And therefore the adaptive immune system is not talking to the cancer, the cancer is not talking to the immune system. You'll find all this in textbooks. You will be told that cancer evades or hides from the immune system. So that is known, it does do that.

But what we think is that makes the cancer vulnerable to, as it were, modern infections, that is infections in the last 400 million years. So cancer is more likely to suffer from infections, bacterial, viral infections, than healthy cells. And I didn't know about this because we were predicting that you should deliberately infect people with virulent microorganisms in order to attack the cancer, having vaccinated them first, you don't want to kill them with smallpox for example, but having given them a vaccination in the first place.

And then my attention was drawn only recently when I was giving a lecture on this stuff in London to the work of William Coley, and I'm going to finish with this story. About 100 years ago standard of care for people treating cancer was to use some cocktail of infection that Coley had prepared. He was struck by the fact that in the early part of the 19th century there were many, many cases of spontaneous remission from cancer in patients who'd had post-operative infection, and that he didn't see many cases around about the turn of the 20th century, and he put that down to the use of sterilised instruments, that we would consider it barbaric to remove a tumour with a rusty razor blade or something, but that's what they used to do in the past. And so he thought that the infection might make the cancer go away, and so he deliberately infected them.

Now, of course that was something considered barbaric, a bit like using leeches, and it sort of dropped out of consciousness, but the truth is that there are many, many case studies where people, including today, where people get infected, the cancer goes away. The standard explanation for that is the exact opposite of what we are saying. The standard explanation is you get an infection, the immune system is boosted and the immune system goes after the cancer as well as the infection. We think it's the exact opposite, we think the cancer isn't talking to the immune system and the cancer is not cured by a boosted immune system, it's cured by the disease, the disease kills the cancer, the immune system saves the patient. So we think it's around that way. So it's a prediction of our theory. We are finding it very hard to get anybody to actually do it, but there are always the mice of course. Thank you.

Robyn Williams: Well done, Paul. You might like to know that the University of Newcastle, New South Wales, there are people who are working on the common cold virus, and of course that renews itself all the time, injected into tumours which then die. Mind you, the work is in progress at the moment, so it's probably worth checking now. I haven't heard from them for at least a year. But we have one question over there please?

Question: Should all this be successful, and you kill cancers which are operating in a way that cells used to operate before multicellular organisms, are you going to destroy the microbiome that supports our life as part of our bodies?

Paul Davies: Cancer remember is not a communicable disease, so everything that goes on, both in the cancer and in the treatment, is confined to one organism. If you're saying are you going to play havoc with the patient's individual microbiome, I would think that any sort of treatment is likely to do that.

But there is a flip side to that, that changing your gut microbiome seems to me (and I think there's good evidence) is clearly a cancer risk because, just very quickly, there are two reasons, one is that I think it can create hypoxic pockets in the gut, but the other is that inflammation and cancer go hand in hand. Inflammation means that the immune system is in overdrive, it means that the organs become leaky, that is that the communication between the bloodstream and the organ is opened up and that enables cancer cells to get in there and so on. So any sort of treatment is going to carry the risks that you upset something, and so of course there'd have to be a trade-off. But there is no direct competition between the cancer cells, these are eukaryotic cells, and the microbiota I've been talking about, which are prokaryotic, they are bacteria or archaea.

Robyn Williams: And that's why poo transplants have proven so efficient.

Paul Davies: Right, faecal transplants is a big deal.

Robyn Williams: Poo transplants are really extremely good if there is a deficiency.

Question: Hi Paul. One question I did want to ask is with all of this cancer, you didn't mention anything about diet or any high amounts of, say, vitamins within that. How does that work?

Paul Davies: Well, just right at the end I said using diet to…now, the standard care for people undergoing chemotherapy is basically to eat well and build up your strength. For people who subscribe to this alternative view, it's the exact opposite; starvation is what is recommended, or the ketogenic diet which is basically the Atkins diet. So Tom Seyfried, who is coming to our next workshop, he's a Boston cancer research and physician, has written a book, Cancer as a Metabolic Disease, and he practices on his students, he gets them to not eat for a week and they seem perfectly happy. And so he advocates…the main thing is to cut down the glucose. So sugar is bad. I think it's bad for diabetes but it's bad for cancer. The problem is that this whole realm of lifestyle and cancer is a minefield of folklore and frankly mumbo-jumbo, and it's really hard to separate out the things that could be taken seriously from just the latest eating fad.

Robyn Williams: Dr Michael Mosley has written a book on this, on the five-by-two diet, he was on The Science Show yesterday, he is on The Science Show again tomorrow.

Question: Amphibians can regenerate their limbs, particularly salamanders, and it's apparently not easy to derail that process, and I wonder how you might want to integrate that.

Robyn Williams: That's the Tufts work, isn't it?

Paul Davies: Yes, and this is interesting because I mentioned I gave a sort of precursory opening address at a big conference that preceded funding these 12 centres, and I thought, well, I don't know anything about cancer, what am I going to say? And then I thought, well, where do you see rapid cell proliferation that is apparently well-managed, and one is embryogenesis and the other is the salamander's limbs. And I mentioned both of these, and an oncologist came up to me afterwards and he said…because I said to this mass audience, hundreds of people, 'Does anybody know anything about salamander limb regeneration?' Blank stares. A guy came up to me afterwards and he said, 'Well, interesting you mention that because I think there was a paper in the 1930s on this.'

Anyway I mentioned the work of Michael Levin at Tufts University, so he has done experiments in which you induce a tumour in the leg of a salamander, so here's a limb, here's a tumour, you cut off the limb through the tumour and then you think, well, when it regenerates the limb, will it be regenerate the tumour? It doesn't, it reprograms the whole thing. So thinks there is an inverse correlation between limb regeneration and embryogenesis and wound healing, inverse correlation between that and cancer. Cancer is sometimes described as the wound that never heals, so it's when a process like that goes a bit wrong that you get something like cancer. But the salamanders sort it all out. It's extraordinary.

Robyn Williams: Thank you.

Paul Davis from the Arizona State University. He talked at the Lorne Cancer Conference this week, that's in Victoria, but the lecture you just heard was at the Adelaide Festival of Ideas.

Next week The Science Show comes from the American Association for the Advancement of Science in Chicago. I'm Robyn Williams.