Category Archives: chromothripsis

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!


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!


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.