Long-live the Revolutions!!

There’s a general view that most folk don’t know much about science and, because almost day by day, science plays a more prominent role in our lives, that’s considered to be a Bad Thing. Us scientists are therefore always being told to get off our backsides and spread the word – and I try to do my bit in Betrayed by Nature, in Secret of Life (a new book shortly to be published) and in these follow-up blogs.

We may be making some progress – and, I have to admit, television has probably done more than me – though I am available (t.v. & movie head honchos please note). As one piece of evidence you could cite the way ‘DNA’ has become part of the universal lexicon, albeit often nonsensically. As evidence I call Sony Corp. Chief Executive Kazuo Hirai, as reported in The Wall Street Journal: “I’ve said this from day one. Some things at Sony are literally written into our DNA …”

Well, of course, that’s gibberish Kazuo old bean – but we know what you mean. Or do we? Most probably couldn’t tell you what the acronym stands for – but that doesn’t matter if they can explain that it’s the stuff (a ‘molecule’ would be better still!) that carries the information of inheritance and, as such, is responsible for all life. Go to the top of the class those who add that the code is in the form of chemicals called bases and there are just four of them (A, C, G & T). Something that simple doesn’t seem enough for all life but the secret is lies in the vast lengths of DNA involved. The human genome, for example, is made up of three billion letters.

A little bit of what is now history …

In the mid-1980s a number of scientists from around the world began to talk about the possibility of working out the sequence of letters that make up human DNA and thus identifying and mapping all the genes encoded by the human genome. From this emerged The Human Genome Project, a massive international collaboration, conceived in 1984 and completed in 2003. I quite often refer to this achievement as the ‘Greatest Revolution’ – meaning the biggest technical advance in the history of biology.

As that fantastic enterprise steadily advanced to its triumphant conclusion, it was accompanied by a series of mini-revolutions in technology that sky-rocketed the speed of sequencing and slashed the cost – the combined effect being an increase the efficiency of the whole process of more than 100 million-fold.

Brings us to the present …

These quite astonishing developments have continued since 2003 such that by 2009 it was possible to sequence 12 individuals in one study. By August 2016 groups from all over the world, coming together under the banner of The Exome Aggregation Consortium (ExAC), have raised the stakes 5,000-fold by sequencing no fewer than 60,706 individuals.

The name of the outfit tells you that there’s what you might think of as a very small swizz here: they didn’t sequence all the DNA, just the regions that code for proteins (exomes) – only about 1% of the three billion letters. But what highlights the power of current methods is not only the huge number of individuals sequenced but the depth of coverage – that is, the number of times each base (letter) in each individual exome was sequenced. In effect, it’s doing the same experiment so many times that errors are eliminated. Thus even genetic variants in just one person can be picked out.

seq-pic

Sequence variants between individuals. For most proteins the stretches of genomic DNA that encode their sequence  are split into regions called exons. All the expressed genes in a genome make up the exomeBy repeated sequencing The Exome Aggregation Consortium have shown that genetic variants in even one person can be reliably identified. Variants from the normal sequence found in four people are shown in red, bold letters.

It turns out that there are about 7.5 million variants and they pop up remarkably often – at one in every eight sites (bases). About half only occur once (which illustrates why DNA fingerprinting, aka DNA profiling, is so sensitive). As Jay Shendure put it, this gives us a “glimpse of the bottom of the well of genetic variation in humans.”

One of the major results of this study is that, by filtering out common variants from those associated with specific diseases, it will help to pin down the causes of Mendelian diseases (i.e. genetic disorders caused by change or alteration in a single gene, e.g., cystic fibrosis, haemophilia, sickle-cell anaemia, phenylketonuria). It’s clear that, over the next ten years, tens of millions of human genomes will be sequenced which will reveal the underlying causes of the thousands of genetic disorders.

The prize … and the puzzle

The technology is breathtaking, the amount of information being accumulated beyond comprehension. Needless to say, private enterprise has leapt on the bandwagon and you can now get your genome sequenced by, for example, 23andMe who offer “a personalised DNA service providing information and tools for individuals to learn about and explore their DNA. Find out if you are at risk for passing on an inherited condition, who you’re related to etc.” All for a mere $199!!

But you could say that the endpoint – the reason for grappling with DNA in the first place – is easy to see: eventually we will be able to define the molecular drivers of all genetic diseases and from that will follow ever improving methods of treatment and prevention.

Nevertheless, in that wonderful world I suspect we will still find ourselves brought up short by the underlying question: how one earth does DNA manage to carry the information necessary for all life?

For those who like to ponder such things, in the next piece we’ll try to help by looking at DNA from a different angle.

References

Ng, SB. et al. (2009). Nature 461, 272-276.

Lek, M. et al. (2016). Analysis of protein-coding genetic variation in 60,706 humans. Nature 536, 285–291.

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New Era … Or Déjà vu?

 

Readers who follow events in the US of A – beyond the bizarre unfolding of the selection of the Republican Party’s nominee for President of the United States – may have noticed that the presidential incumbent put forward another of his bright ideas in the 2016 State of the Union Address. The plan launched by President Obama is to eliminate cancer and to this end $1 billion is to go into a national initiative with a strong focus on earlier detection, immunotherapy and drug combinations. It’s called a Moonshot’, presumably as a nod to President Kennedy’s 1961 statement that America should land a man on the moon (and bring him back!).011316_SOTU_THUMB_LARGE

A key aim of Moonshot is to improve all-round collaboration and to ‘bring about a decade’s worth of advances in five years.’ Part of this involvesbreaking down silos’ – which apparently is business-speak (and therefore a new one on me) for dealing with the problem of folk not wanting to share things with others in the same line of work. So someone’s spotted that science and medicine are not immune to this frailty.silo_mentality

On the home front …

In fact the President could be said to be slightly off the pace as, in October 2015, Cancer Research UK launched ‘Grand Challenges’ – a more modest (£100M) drive to tackle the most important questions in cancer. They’ve pinpointed seven problems and, helpfully, six of these will not be new to dedicated readers of these pages. They are:

  1. To develop vaccines (i.e. immunotherapy) to prevent non-viral cancers;
  2. To eradicate the 200,000 cancers caused each year by the Epstein Barr Virus;
  3. To understand the mutation patterns caused by different cancer-causing events;
  4. To improve early detection;
  5. To map the complexity of tumours at the molecular and cellular level;
  6. To find a way of targetting the cancer super-controller MYC;
  7. To work out how to target anti-cancer drugs to specific cells in the body.

{No/. 2 is the odd one out so it clearly hasn’t been too high a priority for me but we did talk about Epstein Barr Virus in Betrayed by Nature – phew!}.

But wait a minute

Readers of a certain age may be thinking this all sounds a bit familiar and, of course, they’re right. It was in 1971 that President Richard Nixon launched the ‘war on cancer’, the aim of which was to, er, to eliminate cancers. Given that 45 years on in the USA there’ll be more than 1.6 million new cases of cancer and 600,000 cancer deaths this year, it’s tempting to conclude that all we’ve learned is that things are a lot more complicated than we ever imagined.

Well, you can say that again. Of the several hundred genes that we now know can play a role in cancers, two are massively important MYC (‘mick’) and P53. Screen the scientific literature for research publications with one of those names in the title and you get, wait for it, over 50,000 for ‘MYC’ and for P53 over 168,000. It’s impossible to grasp how many hours of global sweat and toil went into churning out that amount of work – and that’s studies of just two bits of the jigsaw!

So 45 years of digging have yielded astonishing detail of the cellular and molecular biology – and that basis will prove essential to any rational approach to therapy. It’s a slow business this learning to walk before you run! But we can be rather more up-beat. Alongside all the science there have come considerable improvements in treatments. Thirty years ago one in four of those diagnosed with a cancer survived for more than 10 years. Now it’s almost one in two. But it’s a hugely variable picture: for breast cancer the 10 year overall survival rate is nearly 80% and for testicular cancer it’s over 98%. However, for lung cancer and cancer rates remain below 5% 1%, respectively. For these and other cancers there has been very little progress.

So 45 years of digging away have yielded astonishing detail of the cellular and molecular biology – and that basis will prove essential to any rational approach to therapy. It’s a slow business this learning to walk before you run! But we can be rather more up-beat. Alongside all the science there have come considerable improvements in treatments. Thirty years ago one in four of those diagnosed with a cancer survived for more than 10 years. Now it’s almost one in two. But it’s a hugely variable picture: for breast cancer the 10 year overall survival rate is nearly 80% and for testicular cancer it’s over 98%. However, for lung cancer and pancreatic cancer rates remain below 5% and 1%, respectively. For these and other cancers there has been very little progress.

All systems go?

Well, maybe. Moonshot is aimed at better and earlier diagnosis, more precise surgery and radiotherapy, and more drugs that can be better targeted. Oh, and bearing in mind that one in three cancers could be prevented, keeping plugging away at lifestyle factors.

How will it fare? Well, now we’re in the genomic era we can be sure that the facts mountain resulting from 45 years of collective toil will be as a molehill to the Everest of data now being mined and analysed. From that will emerge, we can assume with some confidence, a gradual refinement of the factors that are critical in determining the most effective treatment for an individual cancer.

Just recently we described in The Shape of Things to Come the astonishingly detailed picture that can be drawn of an individual tumour when it’s subjected to the full technological barrage now available. As we learn more about the critical factors, immunotherapy regimens will become more precise and the current response rate of about 10% of patients will rise.

Progress will still be slow, as we noted in The Shape of Things to Come – don’t expect miracles but, with lots of money, things will get better.

Transparently Obvious

 

Scientists have a well-earned reputation for doing odd things – by which I mean coming up with a ‘finding’ that leaves me, at least, wondering how, in the name of all things wonderful, they ever got money to do their study. To be fair, it’s the ‘social scientists’ – rather than the ‘real’ lot – that excel in this field. An example? Take your pick. They crop up pretty well weekly in the press. I liked the one on how something called ‘personal congruence’ affects marriage survival. The more congruence you and your partner have the better your chances: if, over time, your congruence goes down the tubes, your relationship will surely follow. But what on earth is congruence? Seemingly it’s a ‘state of agreeing.’ Lots of it equals harmony, loss of it = discord. So, it is what you remember from school geometry: it means more or less equal. Wow! Now I’ve grasped the upshot of this ‘study’: agreeably happy couples tend to make it: pairings based on whacking each other with frying pans tend to end in tears. Why didn’t they tell us earlier!!

Axolotl

   Axolotl

Fortunately, in my world, even the weirdies usually turn out to be quite sensible, once you know what’s going on. Many moons ago a girl-friend asked me if I’d like to see her collection of axolotls. Not having a clue what she was on about I gave it an excited ‘yes please’. Whilst it mayn’t have been what I was hoping for (I was very young back then), I immediately fell in love with these wonderful amphibians that I’d never heard of as she explained what I should have known: these ‘Mexican walking fish’ have very large embryos which makes them particularly useful for studying development. These sensational salamanders really are amazing, not least because they can regenerate entire limbs after they’ve been chopped off.

More recently there’s been another unlikely recruit to the scientific armoury: the zebrafish – a tropical freshwater fish from the Himalayas. This mighty minnow was the first vertebrate to be cloned which led to its being genetically modified to give a transparent variety. That’s all good fun but what on earth is the point of a see-through fish? Well, in Betrayed by Nature we pointed out that you can actually watch tumours growing in transparent zebrafish and we got so excited by that we even included a photo – kindly provided by Richard White of the Dana Farber Cancer Institute in Boston. The cancer was a melanoma which had grown into a black mass about 1 cm in diameter in the fish’s body after a small number of tumour cells had been injected a couple of weeks earlier.

And the driver is …

Nearly 15 years ago, just as the first complete sequence of human DNA was being unveiled, Mike Stratton and his colleagues at the Sanger Centre in Cambridge discovered a mutation that arises in about two-thirds of all malignant melanomas. It’s in a gene called BRAF. The protein made by the gene is an enzyme that’s part of a signalling pathway that pushes cells to divide. The mutation changes the shape of BRAF protein so it works 24/7 as an enzyme: the pathway is no longer controlled by a message from the world beyond the cell. It’s a ‘molecular switch’ that’s been flipped by mutation to act as a cancer ‘driver.’

Richard White and his colleagues showed that the same mutation drove melanoma development in zebrafish and that when it did so something remarkable happened. As the tumours got going they turned on a gene that is normally only required during the first 72 hours after fertilization. The gene’s called crestin – because it’s switched on in a tissue called the neural crest where crestin protein helps to form the bony support for the gills. After that it’s switched off and crestin protein never appears again. Except in the pigment-containing cells called melanocytes when they are turning into a tumour.

Seeing the problem

In a great example of how science can work, Charles Kaufman, Leonard Zon and colleagues in Boston and other centres took this finding and made another transgenic variant of the transparent zebrafish. They cut out the stretch of DNA that controls whether the crestin gene is ‘on’ or ‘off’ and hooked it up to a gene that makes a green fluorescent protein (GFP). Result: when the machinery of a cell turns crestin on, GFP is also made – and the cell glows green under the appropriate light. Hence you would expect to see a glowing neural crest early in development but thereafter a non-glowing fish. Unless it has a melanoma. And Zon & Co saw exactly that. Because green fluorescent protein glows so brightly, a single cell shows up and it turned out that whenever one green cell was detected it always went on to expand and grow into a large melanoma tumour.

1 cell to mel

Tracking a single cell turning into a tumour over 6, 9, 11.5 and 17 weeks. The green fluorescence marks an early developmental gene (crestin) being re-activated in a melanoma tumour (from Kaufman et al., 2016).

But why might it be useful to ‘see’ single cells?

Since the original finding by Stratton & Co more detailed studies have confirmed that mutated BRAF is indeed an important ‘driver’ in about two-thirds of malignant melanoma. But here’s the odd thing: lots of melanocytes (the cells that can turn into melanomas) have mutated BRAF – but they don’t become cancerous. Why not? And there’s something else: it’s well-known that ultraviolet radiation in sunlight causes many melanomas and they do indeed often arise on exposed skin – but they can also crop up in places where, as they say, the sun doesn’t shine. So clearly, important though mutated BRAF and sunlight are, there’s something else that’s critical for malignant melanoma.

The Kaufman experiment was remarkable, not least because it offers a way of getting at this key question of what happens in a cell to kick it off as a tumour, by comparison with a near neighbour that remains ‘normal.’

The tumour cells used in this model carry mutated BRAF and another gene, P53, was knocked out. This gives two major genetic drivers and it may be that further genetic changes aren’t needed. If that’s the case, then the decisive push must come either from epigenetic changes (that affect gene expression without change in DNA sequence) or from adaptations of the tumour microenvironment to provide an optimal niche for expansion. At the moment we don’t know very much about these critical areas of cancer biology. Being able to follow single cells may lead us to the answers.

Keep your eye on the transparent minnows!

Reference

Kaufman, C.K., Zon, L.I. et al. (2016). A zebrafish melanoma model reveals emergence of neural crest identity during melanoma initiation. Science 351, Issue 6272, pp. DOI: 10.1126/science.aad2197

 

Gosh! Wonderful GOSH

Anyone who reads these pages will long ago, I trust, have been persuaded that the molecular biology of cells is fascinating, beautiful and utterly absorbing – and all that is still true even when something goes wrong and cancers make their unwelcome appearance. Which makes cancer a brilliant topic to talk and write about – you know your audience will be captivated (well, unless you’re utterly hopeless). There’s only one snag, namely that – perhaps because of the unwelcome nature of cancers – it’s tough to make jokes. One of the best reviews I had for Betrayed by Nature was terrifically nice about it but at the end, presumably feeling that he had to balance things up, the reviewer commented that it: “..is perhaps a little too light-hearted at times…” Thank you so much anonymous critic! Crikey! If I’d been trying to do slap-stick I’d have bunged in a few of those lewd chemicals – a touch of erectone, a bit of PORN, etc. (btw, the former is used in traditional Chinese medicine to treat arthritis and the latter is poly-ornithinine, so calm down).

I guess my serious referee may have spotted that I included a poem – well, two actually, one written by the great JBS Haldane in 1964 when he discovered he had bowel cancer which begins:

I wish I had the voice of Homer

To sing of rectal carcinoma,

Which kills a lot more chaps, in fact,
Than were bumped off when Troy was sacked.

Those couplets may reflect much of JBS with whom I can’t compete but, nevertheless, in Betrayed by Nature I took a deep breath and had a go at an update that began:

Long gone are the days of Homer
But not so those of carcinoma,
Of sarcoma and leukemia

And other cancers familia.
But nowadays we meet pre-school
That great and wondrous Molecule.
We know now from the knee of Mater
That DNA’s the great creator.

and went on:

But DNA makes cancer too

Time enough—it’ll happen to you.
“No worries sport” as some would say,
These days it’s “omics” all the way.

So heed the words of JBS

Who years ago, though in distress,
Gave this advice on what to do

When something odd happens to you:
“Take blood and bumps to your physician
Whose only aim is your remission.”

I’d rather forgotten my poem until in just the last week there hit the press a story illustrating that although cancer mayn’t be particularly fertile ground for funnies it does gloriously uplifting like nothing else. It was an account of how science and medicine had come together at Great Ormond Street Hospital to save a life and it was even more thrilling because the life was that of a little girl just two years old. The saga brought my poem to mind and it seemed, though I say it myself, rather spot on.

The little girl, Layla, was three months old when she was diagnosed with acute lymphoblastic leukemia (ALL) caused by a piece of her DNA misbehaving by upping sticks and moving to a new home on another chromosome – one way in which genetic damage can lead to cancer. By her first birthday chemotherapy and a bone marrow transplant had failed and the only remaining option appeared to be palliative care. At this point the GOSH team obtained special dispensation to try a novel immunotherapy using what are being called “designer immune cells“. Over a few months Layla recovered and is now free of cancer. However, there are no reports of Waseem Qasim and his colleagues at GOSH and at University College London dancing and singing the Trafalgar Square fountains – they’re such a reserved lot these scientists and doctors.

How did they do it?

In principle they used the gene therapy approach that, helpfully, we described recently (Self Help Part 2). T cells isolated from a blood sample have novel genes inserted into their DNA and are grown in the lab before infusing into the patient. The idea is to improve the efficiency with which the T cells target a particular protein (CD19) present on the surface of the leukemia cells by giving them artificial T cell receptors (also known as chimeric T cell receptors or chimeric antigen receptors (CARs) – because they’re made by fusing several bits together to make something that sticks to the target ‘antigen’ – CD19). The engineered receptors thereby boost the immune response against the leukemia. The new genetic material is inserted into a virus that carries it into the cells. So established is this method that you can buy such modified cells from the French biotech company Cellectis.

105 picAdoptive cell transfer immunotherapy. T cells are isolated from a blood sample and novel genes inserted into their DNA. The GOSH treatment also uses gene editing by TALENs to delete two genes. The engineered T cells are expanded, selected and then infused into the patient.

Is that all?

Not quite. To give themselves a better chance the team added a couple of extra tricks. First they included in the virus a second gene, RQR8, that encodes two proteins – this helps with identifying and selecting the modified cells. The second ploy is, perhaps, the most exciting of all: they used gene editing – a rapidly developing field that permits DNA in cells to be modified directly: it really amounts to molecular cutting and pasting. Also called ‘genome editing’ or ‘genome editing with engineered nucleases’ (GEEN), this form of genetic engineering removes or inserts sections of DNA, thereby modifying the genome.

The ‘cutting’ is done by proteins (enzymes called nucleases) that snip both strands of DNA – creating double-strand breaks. So nucleases are ‘molecular scissors.’ Once a double-strand break has been made the built-in systems of cells swing into action to repair the damage (i.e. stick the DNA back together as best it can without worrying about any snipped bits – these natural processes are homologous recombination and non-homologous end-joining, though we don’t need to bother about them here).

To be of any use the nucleases need to be targeted – made to home in on a specific site (DNA sequence) – and for this the GOSH group used ‘transcription activator-like effectors’ (TALEs). The origins of these proteins could hardly be further away from cancer – they come from a family of bacteria that attacks hundreds of different types of plants from cotton to fruit and nut trees, giving rise to things like citrus canker and black rot. About six years ago Jens Boch of the Martin-Luther-University in Halle and Adam Bogdanove at Iowa State University with their colleagues showed that these bugs did their dirty deeds by binding to regulatory regions of DNA thereby changing the expression of genes, hence affecting cell behavior. It turned out that their specificity came from a remarkably simple code formed by the amino acids of TALE proteins. From that it’s a relatively simple step to make artificial TALE proteins to target precise stretches of DNA and to couple them to a nuclease to do the cutting. The whole thing makes a TALEN (transcription activator-like effector nuclease). TALE proteins work in pairs (i.e. they bind as dimers on a target DNA site) so an artificial TALEN is like using both your hands to grip a piece of wood either side of the point where, using your third hand, you make the cut. The DNA that encodes the whole thing is inserted into plasmids that are transfected into the target cells; the expressed gene products then enter the nucleus to work on the host cell’s genome. There are currently three other approaches to nuclease engineering (zinc finger nucleases, the CRISPR/Cas system and meganucleases) but we can leave them for another time.

The TALENs made by the GOSH group knocked out the T cell receptor (to eliminate the risk of an immune reaction against the engineered T cells (called graft-versus-host disease) and CD52 (encodes a protein on the surface of mature lymphocytes that is the target of the monoclonal antibody alemtuzumab – so this drug can be used to prevent rejection by the host without affecting the engineered T cells).

What next?

This wonderful result is not a permanent cure for Layla but it appears to be working to stave off the disease whilst she awaits a matched T cell donor. It’s worth noting that a rather similar approach has been used with some success in treating HIV patients but it should be born in mind that, brilliant though these advances are, they are not without risks – for example, it’s possible that the vector (virus) that delivers DNA might have long-term effects – only time will tell.

Almost the most important thing in this story is what the GOSH group didn’t do. They used the TALENs gene editing method to knock out genes but it’s also a way of inserting new DNA. All you need to do is add double-stranded DNA fragments in the correct form at the same time and the cell’s repair system will incorporate them into the genome. That offers the possibility of being able to repair DNA damage that has caused loss of gene function – a major factor in almost all cancers. Although there is still no way of tackling the associated problem of how to target gene editing to tumour cells, it may be that Layla’s triumph is a really significant step for cancer therapy.

Reference

Smith, J. et al. (2015). UCART19, an allogeneic “off-the-shelf” adoptive T-cell immunotherapy against CD19+ B-cell leukemias. Journal of Clinical Oncology 33, 2015 (suppl; abstr 3069).

 

Holiday Reading (1) – Molecular Dominoes

As our faithful readers know, the idea in these pieces is to keep up to date with what seem to me to be significant steps along the cancer pathway – a sort of bullet point follow-up to Betrayed by Nature. There’s no doubt that all this keeping pace with exciting developments is great fun but it can leave you a bit breathless – or maybe even worse, liable to loose touch with the basics. So, although this may not be for everyone, I thought it might help some (including me) to take a deep breath and have a couple of items on what you might call “The Story So Far.”

Accordingly, this and the next three posts will be a recap – even better a refresher – a gentle think about the problem that is cancer and how we’re doing. And before you say ‘after umpteen essays’ (96 to be precise but who counts when you’re having fun?) ‘this sounds a bit cart before the horse-ish’ let me just emphasise that the ‘horse’ was really Betrayed by Nature.

Molecular Dominoes

It is now 43 years since President Richard Nixon signed the National Cancer Act, thereby launching what has frequently been referred to as the ‘war on cancer’ in which prodigious sums of money have been committed to the cause of understanding cancer biology and thereby developing more effective treatments. The aim of this is, of course, to eliminate cancers as a major cause of death. It is debatable, to say the least, whether this largesse would have been distributed with quite such gusto had the crystal ball been peered into with sufficient intensity to reveal that in 2015 well over half a million Americans will die from cancers.

That does not sound like an unmitigated success story – nor is it – but the immense amounts of perspiration, sprinkled with the odd moment of inspiration, that have gone into cancer research have yielded a staggering amount of information. Fuelled in particular by the astonishing technical revolution that permits the complete DNA sequences of human genomes (i.e. the genetic code) to be obtained within a day or so, we can now survey in extraordinary detail the molecular basis of this diverse ensemble of diseases that are driven by the acquisition of mutations in components that regulate the fundamental processes of life.

A major objective of all this industry is, of course, to come up with drugs that complement or, ideally, replace surgery and radiotherapy for the treatment of cancers. It’s nearly seventy years since the Buffalo-born pathologist Sidney Farber, working at the Harvard Medical School, launched this odyssey and the intervening period has seen stunning triumphs with remission rates for some formerly untreatable cancers now at nearly 100 percent. But one of the most amazing revelations of all has been the facility with which cancers manage to circumvent drugs designed to kill them. The upshot is that drug resistance is a major limitation to the effectiveness of chemotherapy and most cancer deaths occur because cells outwit the available drugs.

The saga of how tumour cells manage to be so adept at evading mankind’s efforts to skewer them is both fascinating and relevant to all. Like every good story it has a beginning and a middle, which is pretty well where we are at the moment. It will also have an end – although opinions are divided as to what that will be.

In the beginning: Getting the message across

All animals are created and maintained by chemical signals (messengers) telling individual cells what to do. For example: make more cells (proliferate)/make a different type of cell/move to a different location/do nothing/die. Once a messenger contacts the surface of a cell it sets off a game of molecular dominoes: relays of proteins are activated that transfer a signal to the nucleus – specifically to the machinery that reads the coding sequence of genes within DNA and transforms that into proteins. Proteins are the machines of life: workhorses that make things happen so that vast clumps of cells (i.e. living organisms like us) behave in a coordinated fashion.

The signal pathways within cells are complex: best not to Google ‘signalling pathways’ as you’ll be presented with a jumble looking for all the world like a map of the Tokyo subway. But essentially they’re linear stepping stones from membrane to nucleus so it’s convenient to think of them as a telephone system – hundreds of callers (messengers) being put through to the appropriate receivers, i.e. gene targets. Convenient but somewhat misleading as life is rather more complicated. The reason for this is that cells (and with them life) have evolved on a trial and error basis. No bearded electronics whizzo up in the blue yonder sat down with a pencil and paper and designed the ‘best’ circuits that were then assembled in some celestial workshop to remain fixed for all time. Instead we are the result of what in Betrayed by Nature I called the ‘genetic roulette’ of Darwinian evolution. Our signalling pathways resemble the wiring in an old house that has been modified, extended and tweaked by successive owners over many decades. New lights here, a replacement phone line there, etc. with the old cables being disconnected but left in the walls. Animals are much the same except that their redundant wiring accumulates in their genomes, unrequired but lurking and occasionally capable of being reactivated.

Text scheme

Diverse chemical signals activate multiple pathways within cells, ultimately regulating the machinery that reads the genetic code carried by DNA in the nucleus.

These pathways could be thought of as domino runs of different proteins (colored boxes) tripped by the molecular switch of messenger binding to receptor. Rather than acting in isolation, pathways may diverge and/or converge and components may interact, directly or indirectly, giving rise to ‘cross-talk.’ The whole assembly is thus best thought of as a signalling network.

That will do for now: next time we’ll look at what can go wrong.

Blowing Up Cancer

To adapt the saying of the sometime British Prime Minister Harold Wilson, a month is a long time in cancer research. {I know, you’ve forgotten – as well you might. He was PM from 1964 to 1970 and again from 1974 to 1976. His actual words were “A week is a long time in politics”}. When I started to write the foregoing Self Helps (Parts 1 & 2) I had absolutely no intention of mentioning the subject of today’s sermon – viral immunotherapy. But how times change and a recent report has hit the headlines – so here goes.

The reason for my reticence is that this is not a new field – far from it. Folk have been trying to target tumour cells with active viruses for twenty years but efforts have foundered to the extent that the new report is the first time in the western world that a phase III trial (when a drug or treatment is first tested on large groups of people) of cancer “virotherapy” has definitively shown benefit for patients with cancer, although a virus (H101) made by the Shanghai Sunway Biotech Co. was licensed in China in 2005 for the treatment of a range of cancers.

Hard bit already done

I appreciate that getting the hang of immunotherapy in the two Self Helps wasn’t a total doddle – but it was worth it, wasn’t it, bearing in mind we’re dealing with life and death here. My friend and correspondent Rachel Bown had to resort to her GCSE biology notes (since she met me I think she keeps them on the coffee table) but is now up to speed.

Fortunately this bit is pretty easy to follow – it’s just an extension of the viral jiggery-pokery we met in Self Help Part 2. There we saw that using ‘disabled’ viruses is a neat way of getting new genetic material into cells. The viruses have key bits of their genome (genetic material) knocked out – so they don’t have any nasty effects and don’t replicate (make more of themselves) once inside cells. Inserting new bits of DNA carrying a therapeutic gene turns them into a molecular delivery service.

Going viral

In virotherapy there’s one extra wrinkle: the viruses, though ‘disabled’, still retain the capacity to replicate – and this has two effects. First, more and more virus particles (virions) are made in an infected cell until eventually it can hold no more and it bursts. The cell is done for – but a secondary effect is that the newly-made virions spill out and drift off to infect other cells. This amplifies the effect of the initial injection of virus and, in principle, will continue as long as there are cells to infect.

A new tool

The virus used is herpes simplex (HSV-1) of the relatively harmless type that causes cold sores and, increasingly frequently, genital herpes. The reason for this choice is that sometimes, not very often, science gets lucky and Mother Nature comes up with a helping hand. For HSV-1 it was the completely unexpected discovery that when you knock out one of its genes the virus becomes much more effective at replicating in tumour cells than in normal cells. That’s a megagalactic plus because, in effect, it means the virus targets tumour cells, thereby overcoming one of the great barriers to cancer therapy. In this study another viral gene was also deleted, which increases the immune response against infected tumour cells.

All this cutting and pasting (aka genetic engineering) is explained in entertaining detail in Betrayed by Nature but for now all that matters is that you end up with a virus that:

  1. Gets into tumour cells much more efficiently than into normal cells,
  2. Makes the protein encoded by the therapeutic gene, and
  3. Replicates in the cells that take it up until eventually they are so full of new viruses they go pop.

The finished product, if you can get your tongue round it, goes by the name of talimogene laherparepvec, mercifully shortened by the authors to T-VEC (made by Amgen). So T-VEC mounts a two-pronged attack – what the military would call a pincer movement. Infected tumour cells are killed (they’re ‘lysed’ by viral overload) and the inserted gene makes a protein that soups up the immune response – called GM-CSF (granulocyte macrophage colony-stimulating factor). The name doesn’t matter: what’s important is that it’s a human signaling molecule that stimulates the immune system, the overall result being production of tumour-specific T cells.

Fig. 1 Viral Therapy

Virotherapy. Model of a virus (top). The knobs represent proteins that enable the virus to stick to cells. Below: sequence of injecting viruses that are taken up by tumour cells that eventually burst to release new virions that diffuse to infect other tumour cells.

And the results?

The phase III trial, led by Robert Andtbacka, Howard Kaufman and colleagues from Rutgers Cancer Institute of New Jersey, involved 64 research centres worldwide and 436 patients with aggressive, inoperable malignant melanoma who received either an injection of T-VEC or a control immunotherapy. Just over 16% of the T-VEC group showed a durable response of more than six months, compared with 2% given the control treatment. About 10% of the patients treated had “complete remission”, with no detectable cancer remaining – considered a cure if the patient is still cancer-free five years after diagnosis.

Maybe this time?

We started with Harold Wilson and it was in between his two spells in Number 10 that President Nixon declared his celebrated ‘War on Cancer’, aimed at bringing the major forms of the disease under control within a decade or two. It didn’t happen, as we might have guessed. Back in 1957 in The Black Cloud the astrophysicist Sir Fred Hoyle has the line ‘I cannot understand what makes scientists tick. They are always wrong and they always go on.’ To be fair, it was a science fiction novel and the statement clearly is only partly true. But it’s not far off and in cancer there’s been rather few of the media’s beloved ‘breakthroughs’ and a great deal of random shuffling together with, overall, some progress in specific areas. Along the bumpy highway there have, of course, been moments of high excitement when some development or other has briefly looked like the answer to a maiden’s prayer. But with time all of these have fallen, if not by the wayside, at least into their due place as yet another small step for man. The nearest to a “giant leap for mankind” has probably been coming up with the means to sequence DNA on an industrial scale that is now having a massive impact on the cancer game.

When Liza Minnelli (as Sally Bowles in Cabaret) sings Maybe this time your heart goes out to the poor thing, though your head knows it’ll all end in tears. But this time, maybe, just maybe, the advent of cancer immunotherapy in its various forms will turn out to be a new era. Let us fervently hope so but, even if it does, the results of this Phase III trial show that a long struggle lies ahead before treatments arrive that have most patients responding.

We began Self Help – Part 1 with the wonderful William Coley and there’s no better way to pause in this story than with his words – reminding us of a bygone age when the scientist’s hand could brandish an artistic pen and space-saving editors hadn’t been invented:

“While the results have not been as satisfactory as one who is seeking perfection could wish, … when it comes to the consideration of a new method of treatment for malignant tumours, we must not wonder that a profession with memories overburdened with a thousand and one much-vaunted remedies that have been tried and failed takes little interest in any new method and shows less inclination to examine into its merits. Cold indifference is all it can expect, and rightly too, until it has something beside novelty to offer in its favour.”

References

Mohr, I. and Gluzman, Y. (1996). A herpesvirus genetic element which affects translation in the absence of the viral GADD34 function. The EMBO Journal 15, 4759–66.

Andtbacka, R.H.I. et al. (2015). Talimogene Laherparepvec Improves Durable Response Rate in Patients With Advanced Melanoma. 10.1200/JCO.2014.58.3377

Fast Food Fix Focuses on Fibre

If you’re like me you’re probably more bored than absorbed by the seemingly continuous stream of ‘studies’ telling us what we should and shouldn’t eat. No one’s going to argue it’s unimportant but gee, I wish they’d make their minds up. Of course the study of diet and its effects is tricky – as we noted in Betrayed by Nature – not least because you generally need enormous numbers of people to tease out significant effects.

Fortunately authoritative sources like The American Heart Association offer generally sane and simple advice: “eat a balanced diet and do enough exercise to match the number of calories you take in.”

A balanced diet includes fibre, sometimes called roughage, the stuff we eat but can’t digest that assists in taking up water and generally keeping our insides working. There’s much evidence that eating plenty of fibre helps to prevent bowel cancer – usually accumulated from vast numbers (e.g., the European Prospective Investigation into Cancer and Nutrition study involved over half a million people from ten European countries). But even for fibre, when you might just be thinking the answer’s clear-cut, there are other studies showing no protective effect.

So hooray for Stephen O’Keefe and friends from the University of Pittsburgh and Imperial College London for coming up with a dead simple experiment – and some pretty astonishing results (though to prevent panic we should reveal at the outset that they confirm that a high fibre diet can substantially reduce the risk of colon cancer).

Doing the obvious

The experiment compared what happened to two groups of 20, one African Americans, the other from rural South Africa, when they swapped diets for two weeks. So, in principle ‘dead simple’ but to describe it thus does a great injustice to the huge amount of effort involved – for a start they had to find two lots of 20 volunteers willing to have a colonoscopy examination before and after the diet swap. The Western diet was, of course, high protein, high fat, low fibre, whereas the typical African diet was high in fibre and low in fat and protein. Just to be clear, the American diet included beef sausage and pancakes for breakfast, burger and chips for lunch, etc. The traditional African diet comprises corn based products, vegetables, fruit and pulses, e.g., corn fritters, spinach and red pepper for breakfast.

B'fast jpegCompare and contrast.

A rural South African diet (corn fritters for breakfast) and the American diet (Getty images)

Shock – and horror

Almost incredibly, within the two weeks of these experiments there were significant, reciprocal changes in both markers for cancer development and in the bug army – the microbiota – inhabiting the digestive tracts of the volunteers. That is, the dreaded colonoscopy revealed polyps (tumour precursors) in nine Americans (that were removed) but none in the Africans. Cells sampled from bowel linings had significantly higher proliferation rates (a biomarker of cancer risk) in African Americans than in Africans. After the diet switch the proliferation rates flipped, decreasing in African Americans whilst the Africans now had rates even higher than in the starting African American group. These changes were paralled by an influx of inflammation-associated cells (lymphocytes and macrophages) in the now high-fat diet Africans whilst these decreased in the Americans on their new, high-fibre diet.

Equally amazing, these reciprocal shifts were also associated with corresponding changes in specific microbes and their metabolites. You may recall meeting our microbiota (in The Best Laid Plans of Mice and Men and It’s a Small World) – the 1000 or so assorted species of bacteria that have made you their home, mostly in your digestive tract, of which there are two major sub-families, Bacteroidetes and Firmicutes (Bs & Fs). We saw that artificial sweeteners in the form of saccharin shifts our bug balance: Fs down, Bs up. Here feeding Americans high-fibre diet was associated with a shift from Bs To Fs. As we noted before, the composition of the bug army is important because of the chemicals (metabolites) they produce – in this case the diet switch resulted in more short chain fatty acids (e.g., butyrate) in the American group and a reciprocal drop therein for the Africans.

The bottom line

It really is quite remarkable that these indicators of cancer risk manifest themselves so rapidly following a change to a typical Western diet. Of course ‘markers’ are one thing, cancer is another. As one of the authors, Jeremy Nicholson of Imperial College London, said: “We can’t definitively tell from these measurements that the change in their diet would have led to more cancer in the African group or less in the American group, but there is good evidence from other studies that the changes we observed are signs of cancer risk.”

Put less scientifically, “a nod’s as good as a wink to a blind horse.”

Reference

O’Keefe, S.J.D. et al. (2015). Fat, fibre and cancer risk in African Americans and rural Africans. Nature Communications 6, Article number: 6342 doi:10.1038/ncomms7342

Treading the Boards

If I’d asked my friends whether I should consider a debut on the West End stage I know what they would have said. So instead this week I did Cancer Crystal Ball for Robin Ince’s Christmas Science Ghosts at the Bloomsbury Theatre.

Here’s what Bruce Dessau of the London Evening Standard made of proceedings, although the review scarcely does justice to an astonishingly eclectic show!

Bruce Dessau:

Most comedy gigs offer audiences something to laugh about. Robin Ince’s annual Bloomsbury package also offers something to think about. This year’s five-night stint mixes stand-ups and scientists. With a seasonal nod to A Christmas Carol, last night’s show looked at the future.

Ince compered briskly, doing little more than pithy impressions of Brians Blessed and Cox. Having booked a preposterously epic 16 acts he exercised impressive restraint to keep the gig under three hours.

Among the experts doing some crystal ball-gazing were Ben Goldacre, who mounted a persuasive argument for more testing of statins, and cancer specialist Robin Hesketh, who had blood taken onstage — a first for a comedy gig.

Swotty storyteller Josie Long invited fans to do her A-level maths test, while Stewart Lee read from a letter supposedly penned by his 11-year-old self about the future: “There will be even more TV channels … seven. One will be just firework displays.” Joanna Neary’s Björk impersonation skirted around the futuristic theme but was so accurately nutty it hardly mattered.

It was not only the comics who raised a laugh. If you ever wondered what it would be like if Eminem rapped about the brain, catch Baba Brinkman, who closed proceedings by freestyling about neuroscience with his wife Heather Berlin. Conclusive proof that it is possible to be funny and clever.

Risk Assessment

For UK readers a title that instantly raises the spectre of the ’Elf & Safety police and the annoyance, irritation and amusement generated by the seemingly ubiquitous injunctions of their minions. Even my department is not spared, the harbinger of warm weather invariably being an email reminding us that this is no reason for abandoning the rule that at all times we should wear a lab coat – though, to be fair, our local enforcer usually includes the cheeky inference that we retain the option of going naked underneath. Ah, The Joy of Science! ’E & S’s reputation comes, of course, from periodically making the headlines by banning a centuries-old tradition in some rustic backwater involving such fun activities as rolling cheeses down a hill.

Stuart Kettell and sprout

Stuart Kettell and sprout

Mind you, they’ve slipped up recently by allowing Stuart Kettell to push a Brussels sprout up Mount Snowdon with his nose. As that’s 3,560ft (vertically) he probably did lasting damage to his knees, to say nothing of his hooter, as well as inflicting grievous bodily harm on 22 sprouts (they wear out on the basalt, obviously). By his own admission, he’s probably mad – but he did at least raise some money for Macmillan Cancer Support.

 

But why are we bothered about assessing risk?

Setting the above entertainment to one side, estimating risk can be a really serious business and never more so than when it comes to cancer. It’s an especially contentious, long-running issue for breast cancer and both in Betrayed by Nature and more recently in Behind the Screen I tried to crystallize some clear guidelines from the vast amount of available info. In short these were: ignore commercial plugs for thermography – the only test to go for is mammography – i.e. X-ray imaging to find breast cancer before a lump can be felt. And the simple message you were relieved to read in BbN was that, whilst the matter is controversial, if you are offered screening, accept – but be aware that the method is not perfect. There’s a small risk that a cancer may be missed and a bigger chance that something abnormal but harmless will be picked up – a signal for intervention (by surgery and drugs) and that, in those cases, would be unnecessary.

And we’re revisiting this question?

Because there have been some recent contributions to the debate that might well have increased confusion and concern in equal measure for women who are desperately trying to make sense of it all. The most controversial of these comes from a panel of experts (The Swiss Medical Board) who reviewed the history of mammography screening – and recommended that the current programmes in Switzerland should be phased out and not replaced.

Needless to say, their report caused a furore, not only in Switzerland, with experts damning its conclusions as ‘unethical’ – mainly because they ran counter to the consensus that screening has to be a good thing.

So what did the Swiss Big Cheeses point out to get into such hot water? Their view after considering the cumulative evidence was that systematic mammography might prevent about one breast cancer death for every 1,000 women screened. However, two other things struck them. First, it was not clear that this result outweighed the disadvantages of screening – what are inelegantly referred to as the ‘harms’ – the detection and treatment of something ‘abnormal but harmless’ mentioned earlier. Second that, on the basis of a survey by American group, women had a grossly optimistic idea of the benefits of mammography.

Good versus bad

Two of the weightiest bits of evidence that led them to conclude that screening does more harm than good were studies that had combined several independent investigations – what’s called a meta-analysis – which is a way of increasing your sample size and hence getting a more meaningful answer. One of these (The Independent United Kingdom Panel on Breast Cancer Screening) pulled together 11 trials from which it emerged that women invited to screening had a reduction of about 20% in their risk of dying from breast cancer compared with controls who were not offered screening. So far so good. However, inevitably there were differences in methods between the trials, which made the UK Panel very cagey about drawing more specific conclusions but their best estimate was that, for every 10,000 UK women aged 50 years invited to screening for the next 20 years, 43 deaths from breast cancer would be prevented and 129 cases would be over-diagnosed. Over-diagnosis means detection of cancers that would never have been emerged during the lifetime of the individuals and these healthy women will be needlessly subjected to some combination of surgical interventions, radiotherapy and chemotherapy.

The second combined study is from The Cochrane Collaboration, the trials involving more than 600,000 women. Their review also emphasized the variation in quality between different studies and noted that the most reliable showed that screening did not reduce breast cancer mortality. However, less rigorous methods introduced bias towards showing that screening did reduced breast cancer mortality. In this sort of trial “less rigorous” relates particularly to the problem of ensuring that the two groups of subjects are truly randomized – i.e. that nothing influences whether a woman is assigned to receive screening mammograms or not. This is much harder than it sounds, mainly because human beings do the assigning so there is always a chance of either a genuine mistake or a flaw in the design of a particular study. One simple example of how the best laid plans … The consent form for a study specifically states that women are assigned, at random, to either the mammography or no mammography group. Women are then examined by a specially trained nurse. However, if these two steps are reversed, assignment may be biased by the findings of the examination. Precisely such a failure to adhere to a protocol has been revealed in at least one study.

Making the liberal assumption that screening reduces mortality by 15% and that over-diagnosis occurs at a rate of 30%, they estimated that for every 2000 women invited for screening over 10 years, one will avoid dying of breast cancer and 10 will be treated unnecessarily. In addition, false alarms will subject 200 women to prolonged distress and anxiety.

All of which explains why, taking everything into consideration, the Big Cheeses recommended that the Swiss abandon mammography screening.

MammogramWhat does the NHS say?

Actions speak louder than words and in the UK women aged 50 to 70 are invited for mammography screening every three years. By way of explanation, the NHS document (NHS breast screening: Helping you decide) says that for every 200 screened about one life is saved from breast cancer. The American Cancer Society recommends screening annually from age 40 – so it’s clear that Britain and the USA are firmly in favour.

You will have noted that the NHS figure of one saved for every 200 screened is seriously at odds with the findings summarized above and they don’t say where it comes from. However, they are clear about the critical point in saying “for every 1 woman who has her life saved from breast cancer, about three women are diagnosed with a cancer that would never have become life-threatening.”

Misplaced optimism

It will be obvious by now that attaching precise numbers to the effects of screening is next to impossible but the overall message is clear. At best screening yields a small reduction in breast cancer deaths but this comes with a substantially greater number of women who are treated unnecessarily – hence the Swiss position that it is ethically difficult to justify a public health program that does more harm than good.

It’s a bit difficult to assess just how knowledgeable women are about the benefits of mammography screening but one study that tried came up with some positively alarming pointers. A telephone survey of more than 4000 randomly chosen females over 15 years of age in the USA, the UK, Italy and Switzerland revealed that a substantial majority believed that (i) screening prevents or reduces the risk of getting breast cancer, (ii) screening at least halves breast cancer mortality, and (iii) 10 years of regular screening prevents 10 or more breast cancer deaths per 1000 women.

A clear conclusion?

Rates of breast cancer mortality are declining. Hooray! And the five-year survival rate in developed countries is now about 90%. Hooray again! It seems probable that this trend is more though improved treatments and greater awareness – leading to early detection – than because of screening. Nevertheless, all that doesn’t alter the fact that where women are offered the choice they need to be as well informed as possible. The weaknesses of the telephone survey are obvious but the implication that misconceptions are widespread indicates that we need to do much better at explaining the facts of mammography screening.

References

Biller-Andorno N. and Jüni P. (2014). Abolishing mammography screening programs? A view from the Swiss Medical Board. New England Journal of Medicine 370:1965-7.

Independent UK Panel on Breast Cancer Screening. (2012). The benefits and harms of breast cancer screening: an independent review. Lancet 380:1778-86.

Gøtzsche, P.C. and Jørgensen, K.J. (2013). Screening for breast cancer with mammography. Cochrane Database Syst Rev; 6:CD001877.

Domenighetti G, D’Avanzo B, Egger M, et al. (2003). Women’s perception of the benefits of mammography screening: population-based survey in four countries. Int J Epidemiol., 32:816-21.

The Hay Festival

According to the Hay Festival  a recording of my talk ‘Demystifying Cancer’ on Wednesday 28th May should be available on their web site shortly and it can also be heard on the university site. However, I thought it might be helpful to post a version, not least for the for the rather breathless lady who arrived at the book signing session apologising for missing the lecture because she’d got stuck in mud. So for her and perhaps for many others I had the privilege of chatting to afterwards, read on …

 The Amazing World of Cells, Molecules … and CancerOpening pic

One of the biggest influences on my early years was the composer and conductor Antony Hopkins, who died a few days ago. Most of what I knew about music by the time I was 15 came from his wonderfully clear dissections of compositions in the series Talking About Music broadcast by the BBC Third Programme. When he was axed by the Beeb in 1992 for being ‘too elitist’ – yes, they talked that sort of drivel even then – Hopkins might have wished he’d been a biologist. After all, biology must be the easiest subject in the world to talk about. Your audience is hooked from the outset because they know it’s about them – if not directly then because all living things on the planet are interlinked – so even the BBC would struggle to make an ‘elitism’ charge stick. They know too that it’s beautiful, astonishing and often funny – both from what they see around them and also, of course, courtesy of David Attenborough. So it’s not a surprise when you show them that the micro-world of cells and molecules is every bit as wonderful.

The secret of life

What does come as a bit of a shock to most non-scientists is when you explain the secret of life. No, that’s not handing round pots of an immortalization elixir – much better, it’s outlining what’s sometimes rather ponderously called the central dogma of molecular biology – the fact that our genetic material (aka DNA) is made from only four basic units (most easily remembered by their initials: A, C, G and T – humans have over three thousand million of these stuck together). This is our ‘genome’ and the ‘genetic code’ enshrined in the DNA sequence makes us what we are – with small variations giving rise to the differences between individuals. The genetic code carries instructions for glueing together another set of small chemicals to make proteins. There are 20 of these (amino acids) and they can be assembled in any order to make proteins that can be thousands or even tens of thousands of amino acids long. These assemblies fold up into 3D shapes that give them specific activities. Proteins make living things what they are – they’re ‘the machines of life’ – and their infinite variety is responsible for all the different species to have appeared on earth. Can the basis of life really be so simple?

The paradox of cancer

Turning to cancer, a three word definition of ‘cells behaving badly’ would do fine. A more scientific version would be ‘cells proliferating abnormally.’ That is, cells reproducing either when they shouldn’t, or more rapidly than normal, or doing so in the wrong place. The cause of this unfriendly behavior is damaged DNA, that is, alteration in the genetic code – any such change being a ‘mutation’. If a mutation affects a protein so that it becomes, say, hyperactive at making cells proliferate (i.e. dividing to make more cells), you have a potential cancer ‘driver’. So at heart cancer’s very simple: it’s driven by mutations in DNA that affect proteins controlling proliferation. That’s true even of the 20% or so of cancers caused by chronic infection – because that provokes inflammation, which in turn leads to DNA damage.

The complexity of cancer arises because, in contrast to several thousand other genetic diseases in which just a single gene is abnormal (e.g., cystic fibrosis), tumour cells accumulate lots of mutations. Within this genetic mayhem, relatively small groups of potent mutations (half a dozen or so) emerge that do the ‘driving’. Though only a few ‘driver mutations’ are required, an almost limitless number of combinations can arise.

Accumulating mutations takes time, which is why cancers are predominantly diseases of old age. Even so, we should be aware that life is a game of genetic roulette in which each individual has to deal with the dice thrown by their parents. The genetic cards we’re dealt at birth may combine with mutations that we pick up all the time (due to radiation from the sun and the ground, from some foods and as a result of chemical reactions going on inside us) to cause cancers and, albeit rarely, in unlucky individuals these can arise at an early age. However, aside from what Mother Nature endows, humans are prone to giving things a helping hand through self-destructive life-style choices – the major culprits, of course, being tobacco, alcohol and poor diets, the latter being linked to becoming overweight and obese. Despite these appalling habits we’re living longer (twice as long as at the beginning of the twentieth century) which means that cancer incidence will inevitably rise as we have more time to pick up the necessary mutations. Nevertheless, if we could ban cigarettes, drastically reduce alcohol consumption and eat sensibly we could reduce the incidence of cancers by well over a half.

How are we doing?

Some readers may recall that forty-odd years ago in 1971 President Nixon famously committed the intellectual and technological might of the USA to a ‘War on Cancer’ saying, in effect, let’s give the boffins pots of money to sort it out pronto. Amazing discoveries and improved treatments have emerged in the wake of that dramatic challenge (not all from Uncle Sam, by the way!) but, had we used the first grant money to make a time machine from which we were able to report back that in 2013 nearly six hundred thousand Americans died from cancer, that the global death toll was over eight million people a year and will rise to more than 13 million by 2030 (according to the Union for International Cancer Control), rather less cash might subsequently have been doled out. Don’t get me wrong: Tricky Dicky was spot on to do what he did and scientists are wonderful – clever, dedicated, incredibly hard-working, totally uninterested in personal gain and almost always handsome and charming. But the point here is that, well, sometimes scientific questions are a little bit more difficult than they look.

Notwithstanding, there have been fantastic advances. The five year survival rates for breast and prostate cancers have gone from below 50% to around 90% – improvements to which many factors have contributed including greater public awareness (increasing the take-up of screening services), improved surgical and radiology methods and, of course, new drugs. But for all the inspiration, perspiration and fiscal lubrication, cancer still kills over one third of all people in what we like to refer to as the “developed” world, globally breast cancer killed over half a million in 2012 and for many types of cancer almost no impact has been made on the survival figures. In the light of that rather gloomy summary we might ask whether there is any light at the end of the tunnel.

The Greatest Revolution

From one perspective it’s surprising we’ve made much progress at all because until just a few years ago we had little idea about the molecular events that drive cancers and most of the advances in drug treatment have come about empirically, as the scientists say – in plain language by trial and error. But in 2003 there occurred one of the great moments in science – arguably the most influential event in the entire history of medical science – the unveiling of the first complete DNA sequence of a human genome. This was the product of a miraculous feat of international collaboration called The Human Genome Project that determined the order of the four units (A, C, G and T) that make up human DNA (i.e. the sequence). Set up in 1990, the project was completed by 2003, two years ahead of schedule and under budget.

If the human genome project was one of the most sensational triumphs in the history of science what has happened in the ensuing 10 years is perhaps even more dazzling. Quite breathtaking technical advances now mean that DNA can be sequenced on a truly industrial scale and it is possible to obtain the complete sequence of a human genome in a day or so at a cost of about $1,000.

These developments represent the greatest revolution because they are already having an impact on every facet of biological science: food production, microbiology and pesticides, biofuels – and medicine. But no field has been more dramatically affected by this technological broadside than cancer and already thousands of genomes have been sequenced from a wide range of tumours. The most striking result has been to reveal the full detail of the astonishing genetic mayhem that characterizes cancer cells. Tens of thousands or even hundreds of thousands of mutations featuring every kind of molecular gymnastics imaginable occur in a typical tumour cell, creating a landscape of stunning complexity. At first sight this makes the therapeutic challenge seem daunting, but all may not be lost because the vast majority of this genetic damage plays no role in cancer development (they’re ‘passenger’ mutations) and the power of sequencing now means they can be sifted from the much smaller hand of ‘driver’ mutations. From this distillation have emerged sets of ‘mutational signatures’ for most of the major types of cancers. This is a seismic shift from the traditional method of assessing tumours – looking directly at the cells after treating them with markers to highlight particular features – and this genetic approach, providing for the first time a rigorous molecular basis for classifying tumours, is already affecting clinical practice through its prognostic potential and informing decisions about treatment.

A new era

One of the first applications of genomics to cancer, was undertaken by a group at The Wellcome Trust Sanger Institute near Cambridge (where the UK part of the Human Genome Project had been carried out), who screened samples of the skin cancer known as malignant melanoma. This is now the fifth most common UK cancer – in young people (aged 15 to 34) it’s the second most common – and it killed over 2,200 in 2012. Remarkably, about half the tumours were found to have a hyperactivating mutation in a gene called BRAF, the effect being to switch on a signal pathway so that it drives cell proliferation continuously. It was a remarkable finding because up until then virtually nothing was known about the molecular biology of this cancer. Even more amazingly, within a few years it had lead to the development of drugs that caused substantial regression of melanomas that had spread to secondary sites (metastasized).

This was an early example of what has become known as personalized medicine – the concept that molecular analysis will permit treatment regimens to be tailored to the stage of development of an individual’s cancer. And maybe, at some distant time, the era of personalized medicine will truly come about. At the moment, however, we have very few drugs that are specific for cancer cells – and even when drugs work initially, patients almost invariably relapse as tumours become resistant and the cancer returns – one of the major challenges for cancer biology.

It behoves us therefore to think laterally, of impersonal medicine if you like, and one alternative approach to trying to hit the almost limitless range of targets revealed by genomics is to ask: do tumour cells have a molecular jugular – a master regulator through which all the signals telling it to proliferate have to pass. There’s an obvious candidate – a protein called MYC that is essential for cells to proliferate. The problem with stopping MYC working is that humans make about one million new cells a second, just to maintain the status quo – so informed opinion says that blocking MYC will kill so many cells the animal will die – which would certainly fix cancer but not quite in the way we’re aiming for. Astoundingly, it turns out in mice at least it doesn’t work like that. Normal cells tolerate attenuation of MYC activity pretty well but the tumour cells die. What a result!! We should, of course, bear in mind that the highway of cancer therapy is littered with successful mouse treatments that simply didn’t work in us – but maybe this time we’ll get lucky.

An Achilles’ heel?

In defining cancers we noted the possibility that tumour cells might proliferate in the wrong place. So important is this capacity that most cancer patients die as a result of tumour cells spreading around the body and founding secondary colonies at new sites – a phenomenon called metastasis. Well over 100 years ago a clever London physician by the name of Stephen Paget drew a parallel between the growth of tumours and plants: ‘When a plant goes to seed, its seeds are carried in all directions; but they can only live and grow if they fall on congenial soil.’ From this emerged the “seed and soil” theory as at least a step to explaining metastasis. Thus have things languished until very recent findings have begun to lift the metastatic veil. Quite unexpectedly, in mouse models, primary tumours dispatch chemical messengers into the blood stream long before any of their cells set sail. These protein news-bearers essentially tag a landing site within the circulatory system on which the tumour cells touch down. Which sites are tagged depends on the type of tumour – consistent with the fact that human cancers show different preferences in metastatic targets.

These revelations have been matched by stunning new video methods that permit tumour cells to be tracked inside live mice. For the first time this has shone a light on the mystery of how tumour cells get into the circulation – the first step in metastasis. Astonishingly tumour cells attach themselves to a type of normal cell, macrophages, whose usual job is to engulf and digest cellular debris and bugs. The upshot of this embrace is that the macrophages cause the cells that line blood vessels to lose contact with each other, creating gaps in the vessel wall through which tumour cells squeeze to make their escape. This extraordinary hijacking has prognostic value and is being used to develop a test for the risk of metastasis in breast cancers.

The very fact that cancers manifest their most devastating effects by spreading to other sites may lay bare an Achilles’ heel. Other remarkable technical developments mean that it’s now possible to fish out cancer cells (or DNA they’ve released) from a teaspoonful of circulating blood (that’s a pretty neat trick in itself, given we’re talking about fewer than 100 tumour cells in a sea of several billion cells for every cubic millimeter of blood). Coupling this to genome sequencing has already permitted the response of patients to drug therapy to be monitored but an even more exciting prospect is that through these methods we may be moving towards cancer detection perhaps years earlier than is possible by current techniques.

As we’ve seen, practically every aspect of cancer biology is now dominated by genomics. Last picIt’s so trendy that anyone can join in. Songs have been written about DNA and you can even make a musical of your own genetic code, French physicist Joel Sternheimer having come up with a new genre – protein music – in which sequence information is converted to musical notes. Antony Hopkins, ever receptive to new ideas, would have been enthralled and, with characteristic enthusiasm, been only too happy to devote an episode of Talking About Music to making tunes from nature.