How Cancers Form, Cancer Biology and Future Therapies

Scientists have engineered one of the "good bacteria" naturally found colonising the human female genital tract to enable it to produce a chemical called cyanovirin-N, which has powerful anti-HIV effects. Just as some people take probiotic yoghurts as an aid to digestion, the researchers think that their modified bug could be added to the bacterial flora growing naturally in the vagina where it could help to protect the host from infection by the AIDS-causing virus. Cyanovirin-N is naturally produced by a type of blue-green algae called Nostoc ellipsosporum, and it has already been shown in primate experiments to be able to prevent HIV from locking onto and penetrating cells in the vagina. Now, Stanford University's Peter Lee and his colleagues have successfully added the gene for cyanovirin-N to the main chromosome of a bacterium called Lactobacillus jensenii, which naturally colonises the vagina. When the modified bacteria were added to the genital tracts of mice, the researchers were subsequently able to detect small amounts of cyanovirin-N being produced locally. This suggests that it might be possible to use these bugs to provide an effective yet cheap and simple additional line of defence against HIV. This would be especially useful in third world countries such as Africa where several million new cases of HIV infection occur each year, largely because women in these countries have little or no access to effective barrier methods of contraception.

Chris - Now you've all heard of Pop Idol, but now meet the scientific equivalent. It's called Science Idol but it's not scientists strutting around with microphones, so much as pens and pencils. The aim of this competition is to produce a cartoon that will highlight how politicians in America are attempting to distort the conclusions and suppress the results reached by US scientists on issues about things like climate change and pollution. In all over 400 scientists and artists have put pen to paper, and joining us now from the Union of Concerned Scientists to tell us more is Michael Halpern. Why did you need to set this competition up?

Michael - We thought it would be a good idea to set a competition up like this because just like the Ignobel prize, you have the opportunity to laugh at political interference in science and learn a little bit about how important is to decisions.

Chris - But are politicians really meddling in science? Do you believe that?

Michael - We've seen that happen a lot in recent years. The people that lead scientific agencies here in the United States like the Environmental Protection Agency and the Centre for Disease Control have increasingly inserted themselves into the scientific process. I can give you a couple of examples. First of all, climate change. The Bush administration has consistently tried to downplay the threat of global warming and as a result, they've prevented scientists from talking to the press about potential links between hurricane strength and global warming.

Chris - How would you do that though? How would you stop scientists talking to the press? You're talking to us for example. How would they try and stifle the dissemination of the information?

Michael - These scientists that work for federal agencies work under a different set of rules and they are required to only speak to the press when they're allowed to by their superiors, by the political appointees, who are their bosses. If the political appointees don't like what they're going to say, they can tell the scientists not to talk. If the scientists talk then they risk getting fired.

Chris - Now obviously the UK often stands shoulder to shoulder with America. Do you think the same thing is happening here and further afield?

Michael - We haven't done any investigations into what's happening in the UK, but we do know that any sort of interference in the scientific process hurts the way science is done and decreases our capacity to respond to important and complex environmental and health problems.

Chris - Now whilst setting up a cartoon competition is a good way to raise awareness, is making light of the situation when it's actually quite serious the best approach?

Michael - I think it is a very good approach because it allows people to approach the issue in a very accessible way. They see a cartoon and the cartoon pretty much says everything about the issue. Once you've been introduced to the issue then you can really learn a lot more about it.

Chris - I'm just having a look at the winning entry and it's quite funny. It's got a scientist with his pen and pencil in his laboratory and it's got a politician or a bureaucrat holding a grant form. The politician is saying 'you're completely free to carry whatever research you want, as long as you come to these conclusions. This sounds like the mantra from Ford: you can have any colour you want as long as it's black.

Michael - Right, exactly. This is obviously an obsurd sort of practice. Scientists need to come to whatever conclusions the science says, not what the political appointees tell them to do. The artist who drew this cartoon, once he'd one the contest, started getting phone calls and emails from other scientists at his university saying that this is exactly how I feel sometimes and I'm not really allowed to do the research that I want to do.

Chris - So Michael, once you've got your press coverage and people are aware of the situation, how are you going to execute a change, so politicians stop meddling and scientists in America and probably elsewhere are going to stop getting this degree of interference?

Michael - That's a very good question. It's a tough problem to deal with and what we've done is brought a lot of scientists to meet with members of congress and other politicians here in Washington DC to talk about the problem and to educate their members of congress about how important it is to keep the state scientific progress free and unfettered. So we're promoting more protection for scientists in the federal government to be able to publish and speak about their research and just a better way for decision makers to access scientific advice.

Chris - We've devoted tonight's show to the subject of cancer. Lots of people know about cancer because one in three people die of it, but they don't tend to know what it is. So what actually is a cancer?

Gerard - Cancer's probably the best example we've got of evolution in action. Cancer's what happens when cells manage to throw off the shackles that normally restrain them and start to expand. As they expand they evolve and they get worse and worse and eventually people die.

Chris - But why is it that it's so common as a condition and why hasn't the body evolved not to develop cancer?

Gerard - Well the first thing is that it's not that common. Although one in three people get it, cancers arise from single cells and the average human body contains about a hundred thousand million cells, any one of which in principle could become a cancer cell. So in fact, cancers occur in one in a hundred thousand million times in one in three individuals in seventy years, which is very very rare. The reason so many people get cancer is that there are so many cells and you live so long. Really, cancer is suppressed and we have lots of mechanisms to suppress cancer being evolved, but like all evolutionary selection, it only works until we get to reproductive age. Once we've gone beyond reproductive age, evolution doesn't care.

Chris - You say that though but grandmothers have an important role too. I know this because I've recently acquired a new addition to my family and I can tell you that grandmothers are actually quite handy, so there must be some degree of evolutionary pressure to keep grandmothers in the family.

Gerard - Yes it's absolutely true and I've thought about this as well. So maybe in millennia to come humans will get less and less cancer because they'll be selected out as we want granny around. But we're so close to other organisms that don't live very long, and for them the grandparent generation is pretty much irrelevant in terms of care-giving.

Chris - Let's look at why you get cancer though, because it's fair to say that it's a genetic disease, and we're going to be hearing about one of them from Kat Arney who's at the Cancer Research conference this week about a new gene for breast cancer. But why should genes cause cancer? What are the mechanisms involved? What's going on?

Gerard - The thing we have to appreciate is that cancer cells aren't doing anything that normal cells don't usually do. So every time you cut your finger, cells proliferate very rapidly, they generate a blood supply, they recruit other tissues, they rebuild and remodel and mend the cut in the finger. So you have all the machinery you need to become a tumour cell. The point is that it's very guarded and reigned in in normal cells. Cancer is a disease when the mechanisms for reigning in those processes get lost or eroded.

Chris - How does that happen?

Gerard - It happens through mutation and through cosmic rays and various nice things that you eat and who knows what.

Chris - Well even the air that we breath because oxygen causes cancer.

Gerard - That's right. We live in this nasty gas second only to chlorine for how viscous it is, but we've evolved to cope with it. But as I've said, we've evolved to cope with it to a reproductive age and no more.

Chris - We're protected from cancer up to a certain age and we have repair mechanisms to stop the damage from happening. How do they actually work?

Gerard - That's a bit of a mystery actually because as I've said, cancer cells are really only doing what normal cells are doing. You've got all these mechanisms that prevent cancer but how do they tell what's a cancer cell and what's a normal cell. This is actually a deep mystery and we don't really understand that. What we do understand though is when the DNA in the cell gets damaged, there are immediate repair mechanisms that come in and fix the damage - at least as best they can. The problem is that sometimes they make mistakes and that's when you get a mutation. So in some ways you could say that mending the damage is what causes the cancer because that's what's causing the mutations. We also have another response to DNA damage in many cells which is to just trash the cell. That's actually the best way of preventing cancer, but unfortunately if you did that every time you wouldn't have a body left.

Chris - So when we actually have a look at what's going on in a cell, can you just talk us through how a cancer begins? You don't just wake up one morning and have cancer. It obviously has to evolve from somewhere and changes have to accrue. How does that process happen?

Gerard - The clinical disease, of course, is the end point of a whole variety of processes by which time the individual cell that caused the cancer has multiplied and grown and started to erode your normal tissues. The initial events which cause cancer arise in individual cells and they probably happen thousands of times a day, but they never get very far because we have these powerful mechanisms that put the breaks on incipient cancer cells and stop them dividing very early on or kill them.

Chris - What about spread around the body?

Gerard - Why do cancer cells spread around the body? Well a lot of cancers don't, but the ones that bother us do. So the point is that cancers start in one particular site, and they erode the tissue around that site, and if they stay put they're an operable cancer. They're not the things we usually worry about. If they start to break loose and wander round the body and colonise elsewhere, just basically acting like and independent life form, that's when we have the problems.

Chris - You published a paper recently where you had some very interesting things to say about how we might be able to make chemotherapy and radiotherapy a bit more comfortable for people in future. How does that work?

Gerard - I think it goes back to why we aren't able to cure cancers. The truth is, we can kill any cancer that any person has ever had; we just can't keep the patient alive at the same time. We don't have drugs that are sufficiently good at discriminating between the normal cells and the tumour cells. One of the reasons for that is that many normal tissues in the body turn over very rapidly and they're just as sensitive to the cancer treatments as are the cancer cells, and sometimes even more sensitive. If we could preserve those normal tissues and turn down their terrible responses, then we could deliver higher doses of radiotherapy and chemotherapy to the tumour cells and probably kill more cancers. The work that we did recently was looking at what the relationship is between the mechanisms in cells that respond to damage to the DNA, and whether those are the same mechanisms that are widely thought as the mechanisms that prevent tumours occurring in the first place. The idea being that if you have a mechanism that responds to DNA damage by killing the cell, then it prevents it from accumulating mutations and becoming a tumour cell. But our data seem to indicate that the two are actually separate and very different, and you can dispense with the nasty bit, the DNA damage response that kills off all sorts of normal cells, and still retain the tumour repressor functions of this particular protein; a protein called p53.

Chris - Now we're going to join Kat Arney at the National Cancer Research Institute conference in Birmingham. It's the largest UK annual gathering of researchers who work on cancer around the world. Kat's there at the launch today. We're used to having you here in the studio so it's nice to have you out and about. What's this conference all about?

Kat - The National Cancer Research Institute is a virtual cancer institute that has brought together all the major funding bodies of cancer research in the UK. First of all we heard from Mike Richards, the UK cancer tsar, and he gave us a really exciting overview of what the conference is going to be about and how we're going to hear from so many different cancer researchers over the week. Already we're heard from Fran Balkwill, who's here in the studio with me, and she was talking about how we seem to be entering a golden age for cancer research. We also heard news from Mike Richards that we're going to see £35 million given this year for the establishment of seventeen new experimental cancer medicine centres here in the UK and that's funded by Cancer Research UK and the Department of Health. Tomorrow we're going to find out where these are going to be. We're currently sitting here in the back of the lecture theatre listening to the clinical trails showcase and we're going to have new results coming out; successes in bowel cancer and also in breast cancer. And finally, just today, scientists have discovered a new gene for breast cancer. This is pretty exciting stuff because new genes don't come along all the time. But this a new gene called BRIP1 and the researchers have found that this increases a woman's chance of getting breast cancer; roughly doubling it. So by the age of seventy your risk of breast cancer is about 1 in 12, and this found that if you have a fault in the gene BRIP1, you go to a risk of about 1 in 6. They found this by studying about 3000 women.

Chris - How can we have missed this for so long, Kat, given that it's implicated in so many tumours?

Kat - It's something that's known as a low penetrance gene. They think that faulty BRIP1 is found in about 30 000 women in the UK, but it doesn't mean that you're necessarily going to get breast cancer. They think that faults in BRIP1 actually contribute to around 100 cases of breast cancer in the UK every year.

Chris - And will this form part of the screening programme or is this something of academic interest but not clinical relevance?

Kat - At the moment it's very much of academic interest, but it could mean that we could potentially help screen women in the future and it will also inform the development of new treatments and it's important to know about this. The other thing that's really interesting is hearing Gerard in the studio. You might like to know that Gerard lectured me when I was an undergraduate.

Chris - It's a small world isn't it Gerard? Well Kat, I first met Gerard because I was interviewing him for something completely different but in a similar field when he was over in California and we got talking to each other a few months ago and said that you're so good at talking about your subject, you have to come to Cambridge.

Gerard - How could I refuse?!

Chris - So he very kindly agreed to come to Cambridge on his way to Germany to talk to us this evening.

Kat - Well it's absolutely fantastic to hear him back in the UK.

Chris - But you've also got some good news about cancer research in general haven't you, Kat?]

Kat - A couple of weeks ago Cancer Research UK released their most recent funding figures and in the past year we've spent more than £250 million on cancer research. That's entirely from donations from the public, so that's absolutely fantastic news. Also, Mike Richards has announced that there'll be new experimental medicine centres, so that'll be for testing new drugs, getting what we know academically about cancers and turning those into treatments to make a difference for cancer patients in the future. We've got Fran Balkwill here, who's hopefully going to tell us more about how we can use this knowledge and make some genuine progress in cancer research.

I actually had another email about this. It stems from 1907 and it comes from an American doctor, Duncan MacDougall, who tried to work out how much your soul weighs. People have thought for thousands of years that there's some life force or soul that makes us human, and when we die it leaves the body. As it exists, it must be made of something, and if it's made of something then it must weigh something. The easy way to find out how much it weighs is to weigh someone at the moment they die. What he did was to recruit six terminally ill patients, and selected ones that wouldn't thrash around too much at the time of death because that would obviously skew his results a little bit. He had this special bed balance made up and installed into his hospital. One patient lost, he says, three fourths of an ounce, which is twenty one grams. He then published this in American Medicine and it got picked up as 'the soul weighs 21 grams' and there was a massive splash about it. But actually it's wrong, because if you go and examine the rest of his results more carefully, you'll find that there's a little bit of a bias in how he's reported it. One of the people lost 21 grams; two of the people were discounted from the study for 'technical reasons'; a third person lost a load of weight and then put it back on again; and the final two lost a load of weight and then lost a load more, suggesting that they died more than once - I'm not sure! This is where this stems from, and it just shows that if you do careless research it can be quickly picked up and turned into a massive urban myth.

Radiation is everywhere so there's nothing you can do about it. But radiation is bad for cells because you get these high energy particles shooting through your body and through the cells. They damage the DNA directly and they generate these reactive species which further damage the DNA and cause mutations. Most mutations don't cause any problems, but very rarely you'll mutate a gene that's fundamental in regulating cell growth, survival, or where the cell moves and spreads, and then you're on the way to potentially forming a cancer. So in the right places, radiation is good because it can be used in the right places and the right doses to destroy cells. Radiotherapy is used for a variety of cancers, including some brain cancers. Part of the problem seems to be that a lot of the cancer cells, by the time they're presented as a clinical disease, pretty much don't care how much damage they have anymore. In order to become the tumour cell they have, they've had to throw off all the responsive mechanisms that would normally curtail the cell from growing, and you end up with replicating glass beads that you can't do very much about.

It's very difficult to talk about individual cases, and in general it's very hard to say. I just hope that he has very good treatment. It's extremely rare in someone so young. Most cancers in that age group are skin cancer, melanoma and testicular cancer, so I think that it would be very difficult to pin it down on any particular thing.

The idea is that your immune system, which normally fights infection and bacteria, can also respond to any tumour cells that arise in your body. It's something that people have been thinking about for about 50 years. I started my career off as a tumour immunologist, as it's called. I think the jury's still out. There's no doubt that you can raise antibodies and cells that kill enemies; you can raise those against cancer cells. Whether you can do that naturally or whether we can make it happen by manipulating things is still not clear, but it's a very promising area. So in principle the idea is sound; we just don't know how effective it's going to be.