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Monthly Archives: February 2014

Quora activity up to February 2014

Quora is a question-and-answer site. You can view all my contributions here; selected highlights are listed below. I encourage you to check out the other answers submitted for each question, too!

Cancer

Cancer: What is cancer?

Cancer: What are the most common misconceptions about cancer?

Medical Research: When the cure for cancer is discovered, what happens to all of the research centers whose purpose was looking for a cure for cancer?

Cancer: What’s more responsible for the increased incidence of cancer as we age: the failing of our immune system to detect and eliminate the incipient cancers, or the dysregulation of tumor-supressor genes and oncogenes?

Cancer: What is the most elementary form of life in which cancer occurs?

Cancer: What is the difference between “cause cancer” and “increase the risk of cancer”?

Cancer: What is the best drug?

Biology: What prevents Herceptin from binding to HER2 receptors in regular, non-cancerous cells?

Cancer: What possible causes of lung cancer are there besides smoking?

Cancer Research: Are there any health supplements whose intake has been shown to cause cancer or other diseases?

Other Scientific Subjects

Animal Behaviour (Ethology): Why can’t animals learn human languages?

Anthropology: Do phylogenetic studies of humans suggest that there were selective sweeps associated with the adoption of agriculture?

Biology: How do cells know when to stop dividing?

Biology: What is the single most important gene in the human body, and why?

Biology: Why is it that chimpanzees have 99% the same DNA as humans, yet the one percent distinguishes us to such a degree?

Cells (biology): How does a cell know which genes to use?

DNA: How did DNA replace RNA during evolution?

Epigenetics: How do you sequence the epigenome when histone tail acetylation is involved?

Evolutionary Biology: Why do all living creatures have DNA?

Evolutionary Biology: Is natural selection a result of mutation? If yes, then why are these two considered to be different basic mechanisms in the explanation of evolution?

Genetics and Heredity: Why do bands appear on chromosomes where they appear?

Virology: What are some of the most amazing mind-blowing facts about viruses?

About Scientific Research

Scientific Research: What is the initial incentive for a scientist to do research?

Genomics: What should I study in college if I want to get a job in genomics. Do I have to get a PhD? What could I expect as salary right out of college?

Crowdfunding: What if rejected grant proposals were automatically put on crowd funding websites? Do you think this is feasible or a good idea?

Miscellaneous

Jokes: What’s the funniest science-based joke you know?

Best of X: What are the best puns that you made up?

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Posted by on 2014/02/23 in Quora

 

Unbreakable: do superheroes, impervious to cancer, walk among us?

[Originally posted on Occam’s Corner at Guardian Science, in February 2014]

In the 2000 M Night Shyamalan film Unbreakable, Samuel L Jackson’s character – a man born with a severe form of brittle bone disease – asks Bruce Willis’s character, ‘if there is someone like me in the world, and I am at one end of the spectrum, couldn’t there be someone else, the opposite of me at the other end? Someone who doesn’t get sick, who doesn’t get hurt like the rest of us?’ Some cancer researchers are trying to answer the same question; however, in real life, it’s just not that easy to unmask a superhero

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Man of Steel by Steve Mehdi
Steve Mehdi’s ‘Man of Steel’. Photograph: Sheffieldicon/Wikimedia

In June 2013, I described how sequencing the highly abnormal genomes of cancer cells can identify some of the mutations that drive the progress of the disease (and how that’s only the beginning of the story). In the discussion that ensued, reader BlueSky3 commented:

Hope more likely rests in examining the control systems/defence mechanisms of those carrying a hereditary cancer fault which has perhaps persisted in evolutionary time. Not all mutation carriers succumb. Why not?

This comment was so interesting that it’s been percolating at the back of my brain for months. We know that women who inherit a faulty copy of the BRCA1 or BRCA2 gene have a highly elevated risk of developing breast or ovarian cancer – but cancer is not an inevitability. We also know that smokers have a highly elevated risk of developing lung, throat, or oral cancer – but some of them don’t. Why?

The answer lies in the complexity of cancer. The first mutation that starts the first abnormal cell down its path to malignancy can be caused by any number of factors: genetic predisposition, radiation, chemical agents, viruses. Similarly, any number of factors can influence the direction the disease travels thereafter. The first mutated cell has to escape everything the body can throw at it – DNA repair, the shutdown of cell division, programmed cell death, the immune system – before it can become truly dangerous. This complexity creates a number of possible points of intervention. Many, especially those related to the health of the immune system, are at least partially related to lifestyle factors, but in this article I’m going to focus on natural-born superheroes only – that is, those who inherit genetic factors that protect them from cancer.

Unusual suspects

The suggestion to study people with known cancer predisposition mutations who don’t go on to develop cancer is a great one, but not an easy one. If someone is unaware they have such a mutation, and they remain healthy, doctors and researchers have no way to identify them as a subject of interest. Additionally, many people who do know they have such a mutation can now take preventive measures (such as Angelina Jolie’s recent pre-emptive double mastectomy upon learning her BRCA gene mutation status), and we have no way of knowing whether they would have gone on to develop cancer if these measures had not been taken. All this adds up to a very small sample size to study, which makes the identification of subtle genetic correlations extremely difficult. It is possible, however, to search for “superhero” genes among the much larger general population, and to relate some of the findings back to more specialised populations such as those with inherited mutations in BRCA and other cancer susceptibility genes.

Finding Superman

Many years ago, I attended a seminar by local researcher Michael Hayden about using very rare genetic disorders on one end of a spectrum to find new ways to fight very common disorders at the other end of the same spectrum. For instance, Hayden learned of a family with an inherited inability to feel pain, and was able to identify the faulty protein responsible; his lab recently published the results of a preliminary trial of a drug that targets the same protein in people without the disorder, and that may represent an entirely new class of painkillers.)

Unfortunately, finding people with genetic protection from cancer isn’t this straightforward. A person with no ability to feel pain will come to the attention of the medical profession early in life, when they walk for a week on a broken bone or show some other outward sign of their mutation. However, someone with an unusual degree of genetic protection from cancer is unlikely to present in the same way, making it harder to identify the relevant gene variants and to extrapolate from this knowledge to find a way to help prevent cancer in others.

Scientists are a resourceful bunch, though, and we’re starting to make progress despite these limitations. One approach is to look for protective gene variants in the general population, by comparing the gene sequences of people with cancer to those of healthy controls of comparable age and with similar risk factors. For example, in 2004 Angela Cox’s group at the University of Sheffield looked for correlations between breast cancer and the sequences of genes involved in programmed cell death. (This process, also known as apoptosis, is one of the body’s defence mechanisms that a cancer cell must evade if it is to go on to form a tumour. Apoptosis can be triggered by a number of different signalling pathways, each with multiple components; see the diagram for part of the picture.)

TNF signalling pathway
One of many apoptosis signalling pathways. Figure uploaded by:Subclavian/Wikipedia

Cox’s team found that women who’d inherited a variant called D302H in the apoptosis-related CASP8 gene were less likely to develop breast cancer. This variant has since been shown to correlate with a reduced risk of prostate and other cancers, and in 2010 the Group for Assessment of Hereditary Cancer of Valencia Community reported that “CASP8 D302H polymorphism delays the age of onset of breast cancer in BRCA1 and BRCA2 carriers” – making its carriers not unbreakable, but definitely less fragile than the rest of us.

Like so many others, recent technology advances mean that this field of research is now dominated by large-scale whole-genome studies. In 2013, a major European cancer genetics consortium called COGS(Collaborative Oncological Gene-environment Study) published a series of papers describing the results of a massive genome-wide association study of 100,000 cancer patients and 100,000 healthy controls. The study was designed to identify genetic variants that affect the risk of developing hormonally mediated (ie breast, ovarian and prostate) cancers. As expected, most genetic variants were found to increase the risk of cancer, but a few protective variants were also identified. For example, a variant in a component of the telomerase enzyme, which repairs the protective cap structures at the end of chromosomes, correlated with longer caps and reduced risk of some forms of breast cancer, including BRCA-related breast cancer.

The power of whole genome sequencing is also being applied to the study of people of advanced age who’ve avoided the most common causes of death, including cancer. There are a number of “super-ager” studies of this kind under way, including one at my organisation (I’m not involved with the project in any way, but I hear about it in meetings and in conversations at the pub after work). Dr Angela Brooks-Wilson leads the study, which involves sequencing the genomes of people aged 85 or older who are in good health, and who’ve never been diagnosed with cancer, heart disease, stroke, pulmonary disease, diabetes, or Alzheimer’s disease. It’s early days still, but hopes are high.

Back in June, reader BlueSky3 continued:

We are spending millions on dissecting the ‘cancer genome’ in minute detail and on genome wide association studies, shame a bit of the research money cannot be diverted to genetically dissecting the differences between mutation carriers living into their nineties and their less fortunate relatives who succumb to cancer in their thirties

I hope this article has demonstrated that we are in fact making some progress in this direction. We haven’t found our superhero, and I have no last-minute plot twist up my sleeve – but labs full of everyday heroes are on the case, and this story is bound to have many sequels over the years.

 

The cancer genome in context: finding mutations is just the start

[Originally posted on Occam’s Corner at Guardian Science, in June 2013]

Sequencing the genomes of cancer cells lets us identify the mutations that drive the disease and develop drugs that target each mutation. But that’s just the start of the story…
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Nucleosome 1KX5 2
Cancer is caused by changes to the cell’s DNA – but there’s much more to a cancer cell than just its DNA. Image: Richard Wheeler/Zephyris
Cancer is a disease of the genome, initiated by mutations in the genes that usually control cell growth and division.Scientists started to identify the most common mutations found in the most common cancers back in the 1970s, although the limitations of the technology available at the time meant that progress was slow. Drugs that specifically target some of these mutations are already available and prolonging cancer patients’ lives. Now, new technologies such as whole-genome DNA sequencing allow us to identify mutations faster and more cost-effectively than ever before – mutations that are already feeding into the early stages of the drug development pipeline.

The first cancer to have every “letter” of its genome sequenced and every mutation recorded was a leukemia, in a study that was published in the journal Nature in 2008. Genomes of other cancers – lung, breast, melanoma – quickly followed, all also published in top-tier journals and heralded in the media as major breakthroughs. Now, just a few years later, the era of cancer genomics research is well established and single-genome studies are already old hat – it takes much larger studies these days, involving the analysis of dozens of cases, to attract the same kind of attention as the early studies. With the first wave of research behind us, several centres around the world are now starting to study how to incorporate genomics into clinical cancer diagnostics and treatment.

The power and the promise of genomics is that, given enough money, we can start to personalise the treatment given to each patient. For instance, imagine a hypothetical mutation already known to be present in 70% of, say, bone cancers. A targeted drug is developed that works well in that 70% of patients, but does nothing for the other 30%, and whose effects (or lack thereof) take weeks or even months to detect. Sequencing newly diagnosed bone tumours before choosing a treatment lets you give the drug to those who will benefit from it, and find another option for the other 30% without having to put them through weeks or months of futile treatment, complete with nasty side-effects. If you also routinely sequence other types of cancer, you might find that 5% of, say, liver tumours contain the same mutation, and can be successfully treated with a bone cancer drug that might not otherwise be offered to liver cancer patients.

If the history of cancer research and treatment has taught us one thing, however, it’s that things are never quite that simple.

Take the example of a mutation called BRAF(V600E), which is found in a number of cancers, including melanoma. A drug called vemurafenib that targets this mutation has been developed and works well against melanoma, a notoriously aggressive and hard-to-treat cancer. However, when the same drug was given to patients whose colon cancers also contained the BRAF(V600E) mutation, it didn’t work. This puzzle was solved last year by a team who discovered that colon cancer cells contain high levels of a protein called epidermal growth factor receptor that protects them from the effects of vemurafenib; melanoma cells don’t contain much of this protein, which explains the difference in response between these two tumour types.

Chalk this one up as a learning experience for a young field; we now know to look at mutations in the context of the other genes and proteins that are active in the whole cell, not as single entities.

There’s a lot of useful information still to be gleaned from cancer genomes, and – no doubt – a lot of other learning experiences in our future. But with lives on the line, can we find a way to learn these lessons sooner rather than later?

One intriguing option is to pair cancer genomics with a technique called xenografting, which involves inserting a small piece of a patient’s tumour into a mouse. The idea is that the patient’s tumour can be sequenced, promising-looking mutations identified, and candidate drugs (and combinations of drugs) tested against that patient’s tumour in a number of “avatar mice”. This approach can help doctors choose the right treatment for each patient much faster, and with less risk of subjecting them to potentially futile treatments and side-effects; it can also give us early warning of the kind of interplay between a gene mutation and its cellular context seen in the case of BRAF(V600E). As an added bonus, this kind of study – and it is very much in the early research phase at the moment, not part of standard clinical care – can also feed information and tissue samples back to research labs, to help with their work on drug resistance mechanisms and other aspects of the cancer genome in context.

It’s early days for the avatar mouse, a model that is not without its problems. From what I understand of xenografting, it’s as much art as science; some tumour types refuse to “take”, while others start growing immediately. It’s also highly likely that the mix of different cell types within the original human tumour changes during the process of implantation into a mouse, meaning that the transplanted tumour might not respond in the same way as the original. But work is under way, and it is going to teach us a lot.

We will need to explore more than one avenue of investigation to counter the manoeuvres of an ever-evolving enemy. Genomics is a powerful tool that is already helping us to make small advances. Considering the genome in context will take us even further.

 

Feeling crabby about cancer conspiracies

Many internet commenters – and occasionally, random people at parties – think there’s a global conspiracy among cancer researchers to suppress ‘the cure’ as a get-rich-quick scheme. Let’s discuss how silly that is.
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I remember exactly where I was the very first time I learned that I was part of a global conspiracy, raking in millions of dollars and laughing sadistically as people died all around me: I was at my friends’ 2004 Christmas party, and had just told a fellow guest that I was a research scientist and worked at the BC Cancer Agency.

The millions of dollars were news to me, given that as a freshly minted PhD I was making C$35,000 (£22,000) a year at the time. However, what really took me aback was the sheer vehemence of the anger being directed at me by my friends’ new neighbour. He jabbed his finger at me as he raised his voice and ranted about how “all you scientists are sitting on a 100% effective cure for cancer” (“a bunch of vitamins smushed together with proteins” were his exact words), watching millions of people die as we counted the royalty money from the “useless poisons” we were forcing people to take.

The neighbour was ejected from the party, never to be invited back, after poking my husband in the chest when he came to see if I was OK – but I’ve heard that same conspiracy theory many times since. It crops up most commonly online, to the extent that I read even those news articles about my own institute’s latest research findings with a sense of impending doom that worsens as I near the bottom of the page.

Now, I’m not an idiot – I know progress is frustratingly slow (but steady), and I know that some big pharma business practices are rather less than optimally ethical. However, having spent 12 of the last 14 years in academic cancer research (first in the lab and then as a research project manager/grant application wrangler), I also understand why the problem is so hard. (Briefly, killing cancer cells while leaving normal cells unharmed is like trying to win an old fashioned infantry battle in which both sides are wearing the same uniform, except some of the enemy have slightly different shaped buttons, others have slightly longer bootlaces, others have slightly lacier underwear, and all have the ability to suddenly change clothes halfway through the fight).

There is no “cure” – just incrementally earlier detection, more effective treatments, and – in some cases, such as the HPV vaccine – better prevention. We have a long way still to go, but things really are much better than they used to be. (If you’re interested in learning more, I highly recommend Siddhartha Mukherjee’s excellent book ‘The Emperor of All Maladies: A Biography of Cancer‘).

The urge to contribute to further improvements to global cancer outcomes is what drives all the cancer researchers I know to keep going – and that goes for collaborators I’ve met who work in big pharma company labs just as much as for my colleagues in the academic sector. Many of us got into this field in the first place because a loved one succumbed to cancer (my Grandma, in my case, when I was 15).

I know people who’ve turned their backs on much more lucrative medical careers to focus on research; I myself took a pay cut and switched from a permanent job back to the world of short-term contracts to return to academic cancer research after a couple of unfulfilling years in the biotech industry. Believe me, a lot of people could be making a lot more money doing other things. Sure, there are some pretty big egos in research labs around the world, but they’re driven by fame rather than fortune.

More importantly, if we really were sitting on a secret cure, no one in this field or any of our loved ones would ever die from cancer, and that just Is. Not. True. In one recent high-profile example, Dr Ralph Steinman died of pancreatic cancer just days before being awarded the 2011 Nobel Prize in Physiology or Medicine, despite concerted efforts by himself and colleagues to use his own findings to fight the disease. Closer to home, I know dozens of people in both academic and big pharma cancer research who either have had cancer or who have lost someone close to them to the disease.

So. Secret cure? Massive global conspiracy?

Sure.

We’ve managed to buy off every single person involved in the clinical trials we had to conduct to prove that this miracle drug is in fact the cure – all the patients, their families and friends, nurses, doctors, medical records transcriptionists, statisticians, graduate students, etc. We keep our chemotherapy drug royalty profits rolling in by refusing to take the cure ourselves when we get cancer, or to give it to any of our friends or family members. We protect our jobs at the expense of millions of deaths because there’s nothing else this group of highly trained people could feasibly do, no neglected diseases we could work on, once we admit to the world that cancer is cured. And not one person so far has wanted to claim the Nobel Prize and the love and admiration of the entire world that a “cure” would bring them! Wasn’t that lucky?

Oh, and by the way – big pharma are shutting down that other cure you’ve heard about – you know, the super cheap Epsom salt one or whatever the Facebook share of the week is – because there’s no way their huge teams of experienced intellectual property lawyers could possibly find a way to patent a new and unique way to formulate and use an existing product.

But SSSHHHH! Don’t tell anyone…

 

The scientific method, in chromo-logical order

[Originally posted as a guest contribution to GrrlScientist’s blog at the Guardian, in January 2011]

Some people think that science is just all this technology around, but NO it’s something much deeper than that. Science, scientific thinking, scientific method is for me the only philosophical construct that the human race has developed to determine what is reliably true
— Sir Harry Kroto, Nobel Laureate in Chemistry, 2010.

I don’t usually write about the nitty gritty details of new scientific discoveries. Why? Well, because (a) there are so few readers who are interested in them, and (b) I get enough of that kind of thing at work. Last week, though, I read a paper that’s just too good not to share.

My delight with the paper stems not just from the actual findings — although they are very cool — but also with the flow of the piece of work, the “story”. It’s just such a neat and satisfying illustration of how science is done, and why it’s so cool. I intend to focus on this general concept, since so few of you are likely to be interested in the nitty gritty details; if you are interested, the more technical aspects of the post are in italics, for ease of identification (or skipping, depending on reader preference).


Science is awesome. Image courtesy of Eva Amsen.

The paper is titled “Massive Genomic Rearrangement Acquired in a Single Catastrophic Event during Cancer Development”, and it was published in the journal Cell on 7 January 2011. I’ve included the full citation and a link to the paper at the end of this post.

Here’s how you do science:

Play with a shiny new toy…

Not every scientist is a gadget geek who gravitates to the latest sexy technology, but many are. Some people will always make accusations of bandwagon jumping, of playing for the sake of playing; but other people will always be attracted by the possibility that exciting new technology is the path to exciting new discoveries. If the Next Big Thing really does let you do things that weren’t possible before… well, if you can find the right way to apply it, and ask the right questions, you can find some very interesting answers.

One of the coolest new toys in my field is called next-generation sequencing, although I’m not sure why; it’s been around for a few years and should surely be called current-generation sequencing by now. (It’s also — more rarely — known as massively parallel sequencing. Let’s go with that name).

Many scientists (including some of my colleagues, although they weren’t involved with the current study) have started using massively parallel sequencing to explore cancer genomes. This technology allows us, for the first time, to identify every single gene mutation and gene rearrangement present within a tumour. Finding these changes is the first step toward developing new drugs, as well as new genetic tests that help physicians direct the right drugs to the right patients. The first tumour genome sequence was published a couple of years ago, and many more have followed. The authors of this paper are part of this massive sequencing endeavour.

…and use it to discover something new.

You have to be good to be lucky, and you have to be lucky to be good. If you’re using the right techniques in the right way, with the right controls, and if you happen to pick the right samples to analyse, you might just strike gold. In this case the researchers analysed samples taken from ten cancer patients, and uncovered a previously unknown phenomenon that’s only present in around 3% of all tumours.

The authors were sequencing DNA from ten patients with chronic lymphocytic leukemia. In most cases, they found what you’d expect: a limited number of genetic rearrangements, spread out across the whole genome. But in one patient they found a massive number of rearrangements in a small segment of the genome; one arm of one chromosome had gone completely haywire, and contained 42 separate rearrangements.

The next step was to check that this first case wasn’t a one-off. The team scanned hundreds of other tumour cells, from various types of cancer, and found that 2-3% of the tumours contained similar massive rearrangements of either single chromosomes or discrete chromosome segments.

Form a hypothesis and make some predictions…

The novel phenomenon described in this paper doesn’t fit the conventional view of how cancer develops. The authors proposed a different mechanism that would better explain their observations; this mechanism (or model) was their central hypothesis. They then designed experiments that would give one set of results if their hypothesis was correct, and a different set of results if the new phenomenon they’d observed was caused by the conventional mechanism of cancer development.

This process is absolutely key to how science is done. It’s a shame that it’s so rarely laid out explicitly in writing.

The conventional view is that tumours accumulate a series of independent genetic rearrangements over time. However, the rearrangements the team had found looked like the aftermath of a single, dramatic event — a chromosome shattering into many pieces, and being stitched haphazardly back together by the cell’s DNA repair machinery. An event like this would result in distinct types and patterns of genetic rearrangements compared to the patterns caused by a series of changes happening over time.

…and then test them.

Again, this is a crucial part of the scientific method. If your predictions pan out — if your results support your hypothesis — you think up new experiments to test your hypothesis that describes the phenomenon, and keep testing away until you’re either fairly confident in your hypothesis, or until it fails a test. If you experience a failure, you re-think your hypothesis based on the new evidence, and subject it to a new round of tests. Repeat until your results are publishable.

The authors laid out, point by point, why the rearrangements they’d observed fit the single event mechanism better than the progressive change model. They also ran computer simulations of both mechanisms, and found that the results generated by the single event model fit their observations better than did the results generated by the progressive change model.

The hypothesis also predicts that some rearrangements will result in genetic disruptions that cause cancer. The team went back to the cells in which they’d found massively rearranged chromosome segments, and found examples of deletions, amplifications, and other changes to known cancer genes — changes that one would indeed expect to contribute to the development of the disease. Overall, they came up with some very nice evidence to support their hypothesis.

Give your discovery a name…

Naming your discovery is a very rare privilege in science, one I’ve never experienced — I’ve only ever worked on known phenomena involving known genes in known species. I did have some fun with one gene I worked on, called SPAM1 (from SPerm Adhesion Molecule 1), inserting Monty Python references into my research presentations and such, but nothing more creative than that. ( Other scientists have had much more fun with their discoveries).


Image used in one of my research presentations, circa 2004

Having bagged the first published description of catastrophic rearrangements of discrete parts of the human genome, the authors got to name the phenomenon. They chose the word chromothripsis, from the Greek chromos (for chromosome) and thripsis (for shattering into pieces).

…and then tell everyone about it.

This paper isn’t just a description of a novel and exciting finding that happens to neatly illustrate the scientific method; it’s also very nicely written. Scientific papers are subject to certain constraints and conventions, but the standard formats do leave some room for differences in the quality of writing, and for expressions of individual style.

For example, my PhD supervisor (who’s a great scientist, a good bloke, and a Guardian reader. Hi, Dave, if you’re reading!) loves the word “remarkably”. Every time I spot a new paper from his lab, I start scanning the abstract (summary) for a sentence that begins “Remarkably, we found”, and I’m rarely disappointed. This paper goes one better: there’s one instance of “Here we describe a quite remarkable phenomenon”, and also a sentence that begins with “Astoundingly,” which I don’t think I’ve ever seen before.

I suppose if you’ve discovered something novel enough to deserve a new name, you’re entitled to use the word astoundingly.

I also enthusiastically underlined a section that reads as follows:

“the DNA machinery is pasting [hundreds of shards of DNA] together in a helter-skelter tumult of activity”.

Phrases like “helter-skelter tumult of activity” are not part of your standard scientific writing style, but maybe they should be!

Repeat.

The publication of this paper is not the end of the chromothripsis story. It’s barely even the beginning. There’s just enough room for doubt that the hypothesis will need to be subjected to further tests by the original team and by others who’ve read their paper. (This is normal and is part of the scientific process). There are new predictions to be made and tested. There are correlations to be made between this new phenomenon and how the cancer progresses in patients.

Part of the doubt stems from our incomplete knowledge of how chromosomes are broken and repaired in cancer cells; as more pieces of this puzzle are filled in, the new knowledge can be used to design new tests of the chromothripsis hypothesis. And scientists will need to find more evidence for cancer-causing changes induced by chromothripsis before the hypothesis is widely accepted.

However, these caveats needn’t impede the progress of this story. The authors have made a couple of predictions about what causes chromothripsis — ionising radiation, perhaps, or loss of the protective telomere structures found at the ends of chromosomes — and have proposed experiments that would test these predictions (given how long it can take to write a paper and get it published, these experiments are almost certainly already underway, if not complete).

I’d also like to see someone look for correlations between which tumours display evidence of chromothripsis and how the tumour responded to treatment, or whether it came back or spread to another part of the body after initial relapse. These are important clinical questions, and I hope to see some answers appearing in the scientific literature over the next few years.

And so the boundaries of human knowledge expand, slowly but surely.

I left the active research phase of my career behind almost five years ago, but my own miniscule contributions remain a source of immense pride to me. Whatever else I may do in life, the papers in which I described my novel results will still exist as part of the permanent record of human curiosity.

And luckily, I find science to be just as exciting as a spectator sport as it was when I was still working in a lab!

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Full citation:

Stephens PJ, Greenman CD, Fu B, Yang F, Bignell GR, Mudie LJ, Pleasance ED, Lau KW, Beare D, Stebbings LA, McLaren S, Lin ML, McBride DJ, Varela I, Nik-Zainal S, Leroy C, Jia M, Menzies A, Butler AP, Teague JW, Quail MA, Burton J, Swerdlow H, Carter NP, Morsberger LA, Iacobuzio-Donahue C, Follows GA, Green AR, Flanagan AM, Stratton MR, Futreal PA, Campbell PJ. Massive Genomic Rearrangement Acquired in a Single Catastrophic Event during Cancer DevelopmentCell(2011) 144(1):27-40.

 

Facebook rant about Facebook cancer hoax

[Originally posted on my personal blog in February 2013]

I just posted the following on Facebook, and thought I’d share it here, too – the wider the news that this is a hoax is disseminated, the better for everyone.

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I’ve seen a Facebook post about cancer circulating among various completely separate groups of friends in the last few days. The information in the post claims to be from the Johns Hopkins cancer center, but it is most definitely a hoax. I was actually riled up enough to want to write a point-by-point refutation of the contents of the post, but fortunately Johns Hopkins have already done an absolutely stellar debunking job.

This kind of misinformation makes me SO MAD. It twists the available evidence that a healthy diet can reduce (NOT eliminate) the risk of developing cancer into statements that eating or avoiding very specific foods or groups of foods will prevent cancer. This in turn cultivates a culture of victim blaming, in which someone’s response to hearing that someone they know has been diagnosed is often “well, he/she eats [whatever], so of course they got cancer. I don’t eat that, so I won’t”. In fact, outside of some very strongly correlated exceptions (e.g. smoking as a risk factor for lung cancer, some genetic predispositions), it’s next to impossible to blame any individual’s diagnosis on any one factor – it’s a mix of your genes, your diet, your stress levels, your socioeconomic status, your hormones, your environmental exposure, and plain old luck of the draw.

I’ve been kicking around the idea of writing a book about the causes of cancer, to help the newly diagnosed and their loved ones understand what’s going on. Hoaxes like this serve as a kick in the pants to get myself organised and actually do it.

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End rant. But AAARRRGGGHHH!

 

On the Origin of Tumours by Means of Natural Selection

[This was one of the first blog posts I ever wrote, back in June 2007. Originally posted on my old Blogspot site]

I had an interesting conversation with a medical doctor this week. Granted, I’d much rather he’d chosen not to discuss cancer stem cells while removing a suspicious mole from my arm, but these things often seem to happen to me when a physician asks what I do for a living.

Our conversation got me thinking about how the development of cancer mirrors the process of evolution. This comparison first occurred to me during my undergraduate degree in genetics. To understand the molecular nature of cancer, we had to learn to see things from a tumour cell’s point of view.

Cell growth and division are usually very tightly regulated processes; various mechanisms have evolved to ensure that a cell can only divide into two daughter cells if the conditions are right. The correct growth factor chemicals must be present, DNA replication must have been successfully completed, the cell must have reached a certain minimum size, and be in an appropriate position with respect to other cells and tissues.

A tumour develops when these inhibitory mechanisms fail. DNA replication is not 100% accurate, and some daughter cells will receive mutations in genes that usually help to regulate cell division. Most mutant cells will be weeded out and marked for destruction when they fail to meet other cell division criteria, but the occasional gene mutation escapes notice and survives.

Imagine a mutant cell that no longer requires growth factors in order to grow and divide. The cell will divide regardless of its chemical environment, passing on its mutation to both daughter cells, each of which will then divide into two more mutated cells. In this way the mutation is passed down through successive generations of cells. If there are no growth factors present, the mutant cells will continue to divide while normal cells are inhibited. The mutant cells will rapidly come to outnumber the normal cell population. You might say that they have a selective advantage, and therefore produce more offspring.

Eventually, one of the rapidly dividing, growth-factor independent cells will acquire a second mutation in another inhibitory gene. Suddenly, we have a growth-factor independent cell that will divide when it reaches a smaller size than normal. This cell will be able to divide before its merely growth-factor independent relatives are ready. Again, this mutation confers a selective advantage, and subsequent daughter cells will outcompete and outnumber the original population of mutant cells. As cells grow and divide faster and faster, more DNA copying errors creep in. Some of these errors even increase the frequency of further mutations. The end result of this evolutionary process is a clonal population of aggressively growing cells that can move to other locations in the body to produce secondary tumours.

This process is obviously disastrous for the host. But you can not deny that the tumour cells themselves are immensely successful. Their ability to divide more rapidly than the body’s normal cells lets them produce more offspring, and increase the frequency of their beneficial mutations within the total cell population.

The gradual evolution from normal to malignant cells illustrates a very simple natural law. If an individual produces a number of offspring via an imperfect copying mechanism, the result will be a mixed population of individuals with slightly different characteristics. If one of the variants is able to produce offspring faster than its peers, then those offspring will be over-represented in subsequent generations. In this way, characteristics that increase reproductive success are inherited by more individuals and continue to increase in frequency, gradually changing the overall demographics of the population.

This really should be self-evident, and I have a very hard time understanding why evolution deniers find the concept so difficult to grasp. The gradual accumulation of mutations during cancer development is well documented, but I don’t think I’ve ever seen these data used to teach the principles of evolutionary theory. I fear that I would not make a very good teacher myself as I would become too easily frustrated with those who just can’t seem to get it. But if anyone reading this is involved in science education, please let me know what you think.

Oh, the suspicious mole turned out to be only slightly dodgy. No matter how cool evolution is, I’m happy to avoid observing the survival of the fittest within my own puny Celtic skin.

 
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Posted by on 2014/02/23 in cancer, evolution, stem cells