Category Archives: cancer

Quora contributions from August 2016 to March 2017

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!


What molecular mechanisms regulate methylase activity?

Why is the epitranscriptome (epigenetic marks on mRNA) important when mRNA molecules last so transiently?

What is the difference between histones and nucleosomes?

What’s “Histone modification”?

What is the difference between acetylation and methylation?

Why does acetylation remove the positive charge on histones?

Why does trimethylation of histone H3 on lysine 27 (K27) result in chromatin repression?

Should histone modifications be labeled as an epigenetic modification? Or just a chromatin modification?

Are epigenetics a type of post-translational modification?

Could stem cells just be epigenetic?

I want to start learning about epigenetics. Where should I start?

What are the best books on epigenetics, for a layperson?


Can cancer cells evolve resistance to treatment?

Why are familial tumors usually multiple compared to sporadic cases, even when the same mutation is responsible for both types?

Why can’t people with cancer donate their organs?


Can we use mRNA silencing techniques to inhibit the HIV genome?

Other scientific topics

Once we insert a desired gene into the human genome, how is its expression limited to the specific target organs where the gene is needed?

Do our parents have the same DNA as us?

Do red blood cells have functional miRNAs?

My ex-husband and I both have blood type O (positive and negative). How is it possible that our son has type B+?


Do you think Goodreads should ask a few questions from a book before letting anyone rate it?





“Cracking Cancer” on CBC’s The Nature of Things tonight

Tonight’s episode of CBC documentary series The Nature of Things with David Suzuki features an in-depth look at the BC Cancer Agency’s Personalized Onco-Genomics (POG) project, which is exploring the feasibility of sequencing DNA and RNA from cancer cells to help physicians select the best treatment for each individual patient.

Project co-lead Dr. Janessa Laskin also did a great interview about POG on CBC Radio’s The Current yesterday.

I got to see a staff preview of the Nature of Things episode on Tuesday, and I think the production team did an amazing job at presenting a balanced view of this specific project and of cancer genomics in general. If you’re in Canada, check it out on the CBC tonight at 8pm! It’ll be repeated on Saturday, and available online at the link above.

NB I’m not directly involved with this project, but pretty much everything we do in my department (Canada’s Michael Smith Genome Sciences Centre) touches on POG in some way. Many of my colleagues and friends are featured in the documentary – it’s always very cool to see people you know on TV! We’re all very proud of the work we do; I hope you enjoy seeing inside our world!


Quora activity for January 2015 – August 2016

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!


Would it be possible to avoid cancer by modifying our DNA?

Is whole genome sequencing of any use in cancer diagnostics?

If our body can detect cancerous cells, why do people still get cancer? Does it mean that we can improve our body’s defenses against cancer before even getting sick?

If 2/3 of cancers are caused by chance mutations, why should I work to help prevent cancer?

Is it possible that cancer is not actually a disease to be “cured”, but it is actually an inherent defect of genetics?

Is cancer an intrinsic feature of life?

Is worrying about cancer the biggest cause of cancer?

What are the chances (if any), that a blind person getting cancer in the eye would allow them to see again?

What cure would be most beneficial to discover: HIV/AIDS or cancer?

Can Ebola be treated with cancer drugs?


If two people have identical DNA fingerprints, what other molecular evidence does forensics use to distinguish between biological samples?

Can a methylation pattern be sequenced?

What could potentially be the most exciting application of epigenetic research?

Why hasn’t Lamarck been acknowledged in the face of the burgeoning advances made in the science of epigenetics?

In what way does histone methylation prevent transcription?

Is the epigenetic system of a person heritable?

Is there a meaningful way to diagnostically test a patient for epigenetic changes caused by long term use of medications?

Other Scientific Subjects

Is it a possibility that parents of genotype AA have an offspring with AS?

What is the reason that viruses are inactive when not inside any organism? What is the mechanism?

Will the final solution to HIV be to just accept it as part of the human genome?

What can you tell about a gene based on its tissue expression patterns?

What are some interesting examples of people becoming infected with typically fatal diseases (e.g. Ebola, HIV/AIDS, rabies, anthrax) through unusual means or at long odds?

Could cellular environment (pH, temperature, molecular crowding, redox state) affect a cell’s interactome?

What causes mutation in viruses?

Which (multicellular) animal is most deadly to humans?

What would happen if all the DNA in my body suddenly disappeared?

What are the most useful lab hacks, tips and tricks for molecular biology/biochemistry?

Do viruses have nutritional value for any organism?

What will next-generation sequencing be called a generation from now?

When will we be able to sequence the genome of every living vertebrate on Earth?

What are the oddest organisms?

Biochemistry: Why does the yeast two-hybrid system system have low specificity?

About Scientific Research and Careers

What does a principal investigator at a molecular biology lab spend time doing during the day?

How common is it for scientists to hire people to write their grant proposals?

How do I improve my grant writing?

I want to apply for a grant for a project, but I have no idea how to write a proper grant proposal. How can I go about this?

What is your favorite annual scientific conference?

Does a biochemist/biologist have to know all the reactions of cellular respiration or other general topics by heart after graduating?


Is there racism in Canada? Why?

What’s the best story about “fighting fire with fire”?

What are some of the best moments while taking exams?

Why do people believe in the ancient aliens theory?

If cloning of people was legal, whom would you choose and why?

What are some great optical illusions?

Which is the best way to pass the PMP exam?

Why do some people choose to use Quora over writing a blog?


Can a trigger-happy immune system cause cancer after viral infection?

(Originally published on Occam’s Corner at Guardian Science, in June 2014)

Friendly fire: while the immune system tries to protect us from viruses, it could be causing cancer

The immune system is a fickle thing, both hero and villain.

The ability of our ancestors to survive plague and pestilence was one of the forces that shaped the evolution of the human species into its current form. But many of us now find ourselves in environments where many of the biggest infectious threats have been neutralised by a combination of vaccination programmes, improved hygiene, and (temporarily) effective treatments. With their usual duties cut back so drastically, our evolutionary superstar immune systems sometimes lash out at innocuous perceived threats. This can cause allergies, multiple sclerosis, and other auto-immune disorders in the process – sins of commission, if you will.

But at least our immune systems are still pretty good at protecting us from infections and most cancers, right?

Well, much of the time, yes. The importance of the immune system in protecting us from cancer is evident from the increased rates of the disease in people with reduced immunity due to HIV/Aids or followingorgan transplants. And yet the immune system’s sins of omission mean that far too many cancer cells slip through the net – and we still get colds and the dreaded norovirus, too.

This week, though, new research from University College London (UCL) suggests for the first time that the immune system also commits sins of commission when it comes to cancer.

The research, published in the journal Cell Reports on Thursday, concerns a class of genes called the APOBEC family. These genes code for proteins that attack invading viruses by mutating their DNA, a tactic that can stop or at least slow the replication and spread of the virus. The mutations caused by APOBEC proteins occur in a characteristic pattern – a pattern that also shows up in some types of cancer, including types that are often caused by infection with human papilloma viruses (HPV). Could the mutations in these cancers be caused by misfiring antiviral defences?

Papilloma Virus (HPV) EM
Human papilloma virus. Photograph: Laboratory of Tumor Virus Biology/Wikimedia Commons

Drs Stephen Henderson, Tim Fenton and their teams at UCL have now demonstrated that there is indeed an association between the presence of HPV in some cancer cells, elevated activity of the APOBEC proteins in those cells, and the presence of the characteristic APOBEC-mediated mutation pattern. These findings support the idea that HPV infection triggers an anti-viral attack that not only hits the intended target – the viral genes –but also the cell’s own DNA. The UCL team also found that mutations caused by APOBEC have a strong tendency to hit genes such as PIK3CA that help to regulate the growth and division of the cell, and whose mutation is associated with the development of cancer.

“It is not clear why HPV infection causes the APOBEC genes to misbehave and mutate PIK3CA,”says Dr Henderson. “It could be that the body responds to HPV infection with increased ABOBEC activity, simply making ‘friendly fire’ more likely. Alternatively, there may well be something about the virus that causes the APOBEC response to wrongly target the body’s own genes for mutation.”

The good news is that these new findings open up new avenues for researchers working on diverse aspects of the cancer problem: there are known inherited variations in a member of the APOBEC family that have been linked with an elevated risk of developing breast cancer; other viral infections may also be associated with cancer, possibly via the same mechanism; and drugs that target mutated versions of the PIK3CA protein are already being developed.

Meanwhile, if you don’t want to give your trigger-happy immune system a shot at the human papilloma virus, effective vaccines are now available.

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Posted by on 2014/09/14 in cancer, genetics, viruses


Epigenetics part 2: cancer, chaos and chemo

(Originally published on Occam’s Corner at Guardian Science, in June 2014)

As explained in part 1, epigenetics — chemical modifications to DNA and proteins – can profoundly affect gene activity. But epigenetics also plays an important role in cancer, and research in this field may be opening up potential new treatment options.

There are many different types of cell in the body. With very few exceptions, our cells contain identical DNA, but have different levels of activity of each of the genes encoded in that DNA. A gene that’s switched on at low levels in the intestine might be highly active in the brain and completely silent in the liver. Epigenetic marks (chemical modifications of the DNA or of the histone proteins that bind it — see part 1) help to set and maintain the appropriate levels of gene activity for each cell.

Histone modifications are very dynamic, allowing for rapid changes to the activity of specific genes in response to outside stimuli; in contrast DNA modifications, primarily a mark called DNA methylation, are much more stable. The epigenetic mechanisms that regulate both kinds of marks are like cogs in a well-oiled machine, working together with other parts of the cellular apparatus to keep everything running smoothly.

Cells affected by diseases have abnormal levels of gene activity. For example, the activity of the various tumour suppressor genes that usually inhibit cell growth and division might be lost in a cancer cell, while pro-division genes might be hyperactive. The epigenetic marks and mechanisms found in such cells also look very different to those present in their healthy counterparts. In cancer cellsfor instance, the overall amount of DNA methylation decreases as the disease progresses, even while specific parts of the DNA near important genes experience abnormally high levels of methylation; the patterns of histone modification observed in cancer cells also deviate more and more from the normal baseline over time.

There are also characteristic epigenetic changes in many inflammatory and autoimmune disorders, conditions associated with ageing, and many others. However, I’m going to focus on cancer in the rest of this article, since that’s the field I know best.

Epigenetic changes in disease: cause or effect?

A cancer cell is a chaotic beast. Freed from the multiple layers of regulation that usually control its growth and division, everything from its molecules to its movements is abnormal. Teasing apart the abnormalities that contribute to the chaos from those that are just collateral damagecaused by the chaos has proven to be a difficult problem to solve, and epigenetic abnormalities are no exception to this general rule.

It’s likely that many of the altered epigenetic patterns observed in cancer cells are just noise, a response to the chaos caused by other, earlier, changes. However, there’s evidence that in some cases epigenetic changes can actively contribute to the progression of the disease, and are sometimes even the very first event that sets a cell off on its path to malignancy:

  • Changes to the activity of specific genes that are usually involved in controlling cell growth can sometimes be attributed at least in part to epigenetic changes. The BReast CAncer (BRCA) genes, and other examples of the tumour suppressor genes that usually control cell growth, are often silenced by DNA methylation in cancer cells; conversely, the epigenetic marks that usually keep pro-growth genes silent in normal cells can be removed in cancer cells.
  • Mutations in proteins that create, remove, or bind to specific epigenetic marks have also been found in malignant cells; some of these mutations may even be the first alteration to occur in some types of cancers. For example, researchers (including some of my former and current colleagues) have identified a mutation in an epigenetic regulator protein called EZH2 in some types of lymphoma. The mutation changes the activity of EZH2, making it create more of a type of histone modification that’s associated with gene silencing. This seems to be a very early event in the development of these types of cancer. Mutations in other genes that are involved in forming, removing, or recognising specific epigenetic marks are also quite common in additional forms oflymphoma and other cancers.

Epigenetic therapies

There are two main targets when trying to reverse the epigenetic changes that contribute to the initiation and progression of cancer: the altered epigenetic marks themselves, and the abnormal proteins (such as mutated EZH2) responsible for initiating and maintaining these changes. In my last article, I compared the patterns of epigenetic marks found in different parts of the genome to using a pack of highlighters to mark up different parts of a text for different kinds of follow-up; to extend this analogy, epigenetic therapies try to either erase any coloured ink that has ended up on the wrong part of the text, or to fix the broken highlighter pen itself.

Given how hard it can be to distinguish epigenetic signal from noise in a cancer cell, and how critical epigenetic marks are to the normal function of healthy cells, the first of these two approaches – targeting the altered epigenetic marks found in cancer cells – is a more complicated and risky approach. Removing an epigenetic mark that’s present at abnormally high levels in cancer cells, but only as a reaction to the processes that are actually driving the progression of the disease, won’t effectively treat the cancer; decreasing the overall level of an epigenetic mark across the whole genome when only its effects on a couple of genes are actually important runs the risk of causing a lot of new collateral damage.

However, despite these difficulties it has been possible to design drugs that function by reversing global changes to DNA and histone modifications. Some of them are already in use, with many more in development.

The first such epigenetic-based cancer therapies to be approved are from a class known as histone deacetylase (HDAC) inhibitors. These drugs increase the overall level of a specific type of histone modification, and can reactivate some of the tumour suppressor genes that are silenced in certain cancer cells. The details of exactly how these drugs work are still being investigated (interestingly, their epigenetic effects may not represent the full story), but HDAC inhibitors have been shown to have a beneficial effect against some cancers, especially in combination with other therapies.

Drugs that reverse the gene silencing caused by DNA methylation in cancer cells are also in development, although at an earlier stage of the testing process. The benefits of these drugs are accompanied by the same kinds of side effects seen with other chemotherapy agents, but as the field matures and new classes of drugs enter the development pipeline, there is hope that these problems can be mitigated.

The second approach to epigenetic therapies – targeting the “broken highlighters” directly – mirrors a general trend in cancer therapy to develop drugs that target a specific protein. The goal is to drastically reduce the number and severity of side effects compared to those caused by traditional chemotherapy drugs, which are less precisely targeted and cause more collateral damage to the body’s healthy cells.

When a rogue protein (such as the form of mutated EZH2 seen in some lymphomas) is spreading epigenetic chaos in the cell, and when there’s good evidence that the resulting changes contribute to the progression of the disease, then inhibiting that protein would be expected to be an effective anti-cancer therapy.

Indeed, drugs that specifically block the function of the mutated EZH2 protein are in development. In early tests in cultured cancer cells and in mouse models, the EZH2 inhibitor reversed the altered pattern of epigenetic marks, restored the activity of the genes silenced by these marks, and slowed the growth of the lymphoma cells (NB my institution was not involved in this study).

Similar work is being done with the other “highlighter pens” that are known to often malfunction in cancer cells.

Given how long the drug development and testing process is, and how many potential drugs fail along the way, I’d call this a field with a lot of promise – in the long term. Researchers are still working out the details of how hundreds of proteins work together to set and maintain the patterns of epigenetic marks needed in a healthy cell, and the ability to tweak this complex machinery to turn a specific gene on or off at will is still a long way away. However, the ability to target and reverse the epigenetic chaos caused by mutations in specific epigenetic regulators is certainly a good place to start, and it’s encouraging to see such a relatively new field of basic research already reaching the clinic.

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Posted by on 2014/09/14 in cancer, epigenetics


Cancer Research UK busts ten persistent cancer myths

The charity Cancer Research UK recently published a great piece titled “Don’t believe the hype – 10 persistent cancer myths debunked”.

The article takes a common-sense approach, backed up by the latest scientific findings, to discussing some of the most common myths that surround the disease. These include the beliefs that acidic diets cause cancer, that sharks don’t get cancer, and that there’s a secret cure for cancer that’s being suppressed (something I’ve written about before, too).

I don’t know how these myths get started, but they’ve been around since I can remember, and they seem to propagate faster than ever through Facebook and other channels. I find that the Cancer Research UK website is usually a great starting point if you want to fact-check a claim about the disease. I also highly recommend the book The Emperor of All Maladies: A Biography of Cancer by Dr. Siddhartha Mukherjee; I’ve been in cancer research since 1998, so I knew much of the science described in the book, but not the story of how we gained this knowledge of the disease. It’s a fascinating read.

Check out the full Cancer Research UK article here

Full disclaimer: I did my PhD at a Cancer Research UK-funded facility, but have had no formal connection with the charity since 2002. I just really like their website and podcast 🙂


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


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…
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.

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?


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!


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.