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


Quora activity for May 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!


How would you explain to a layperson why cancer has been such a difficult medical problem to solve?

Are cancer cells organisms?

Can you name some practices that cause cancer that people do without knowing?

Is chemotherapy effective in late-stage cancers?

Why is nausea often a side effect of receiving chemotherapy?

Other Scientific Subjects

What non-standard model organisms are currently used in experimental biology?

Should genetic engineering be banned?

Is AIDS a virus or cancer of the human blood?

Do human beings have unique toe prints, similar to unique fingerprints?

Doesn’t a person’s body reject embryonic stem cells from another person?

When will HDAC inhibitors be available for humans?

About Scientific Research and Careers

Writing Grant Applications: How do funders measure their grant’s impact?

What is the most annoying thing people have asked you after you told them your decision to do a Ph.D.?


What are some funny stories you have about your name being mispronounced or misspelled?

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Posted by on 2014/06/07 in Quora


Epigenetics 101: a beginner’s guide to explaining everything

[Originally published on Occam’s Corner at Guardian Science, in April 2014]

The word ‘epigenetics’ is everywhere these days, from academic journals and popular science articles to ads touting miracle cures. But what is epigenetics, and why is it so important?

Epigenetics is one of the hottest fields in the life sciences. It’s a phenomenon with wide-ranging, powerful effects on many aspects of biology, and enormous potential in human medicine. As such, its ability to fill in some of the gaps in our scientific knowledge is mentioned everywhere from academic journals to the mainstream media to some of the less scientifically rigorous corners of the Internet.

  • Wondering why identical twins aren’t actually, well, identical?Epigenetics!
  • Want to blame your parents for something that doesn’t seem to be genetic? Epigenetics!
  • Got a weird result from an experiment that doesn’t seem to make sense? Epigenetics!
  • Want to think yourself healthy? That’s not epigenetics! (Sorry ‘bout that).

But what exactly is epigenetics – and does the reality live up to the hype?

Screen Shot 2014-05-04 at 5.37.45 PM

The incidence of the word ‘epigenetics’ in published books, 1800-2008, via Google ngrams. Bringing this graph up to date and including other publication types would send that line right off the top of your screen.

Epigenetics is essentially additional information layered on top of the sequence of letters (strings of molecules called A, C, G, and T) that makes up DNA.

If you consider a DNA sequence as the text of an instruction manual that explains how to make a human body, epigenetics is as if someone’s taken a pack of highlighters and used different colours to mark up different parts of the text in different ways. For example, someone might use a pink highlighter to mark parts of the text that need to be read the most carefully, and a blue highlighter to mark parts that aren’t as important.

There are different types of epigenetic marks, and each one tells the proteins in the cell to process those parts of the DNA in certain ways. For example, DNA can be tagged with tiny molecules called methyl groups that stick to some of its C letters. There are proteins that specifically seek out and bind to these methylated areas, and shut it down so that the genes in that region are inactivated in that cell. So methylation is like a blue highlighter telling the cell “you don’t need to know about this section right now.”

DNA doesn’t just float around the cell by itself; it wraps itself around a group of proteins called histones. There are some epigenetic marks that actually affect these histones, rather than the DNA itself.

The DNA double helix wrapped around four histone proteins, in a structure called a nucleosome. By Richard Wheeler (Zephyris) [CC-BY-SA-3.0]]/Wikimedia Commons

Methyl groups and other small molecular tags can attach to different locations on the histone proteins, each one having a different effect. Some tags in some locations loosen the attachment between the DNA and the histone, making the DNA more accessible to the proteins that are responsible for activating the genes in that region; this is like a pink highlighter telling the cell “hey, this part’s important”. Other tags in other locations do the opposite, or attract other proteins with other specific functions. There are epigenetic marks that cluster around the start points of genes; there are marks that cover long stretches of DNA, and others that affect much shorter regions; there are even epigenetic modifications of RNA, a whole new field that I’m simultaneously fascinated by and trying to ignore because it’s bound to create a lot of extra work for me in both the project manager and the grant writing parts of my role. There are no doubt many other marks we don’t even know about yet.

Even though every cell in your body starts off with the same DNA sequence, give or take a couple of letters here and there, the text has different patterns of highlighting in different types of cell – a liver cell doesn’t need to follow the same parts of the instruction manual as a brain cell. But the really interesting thing about epigenetics is that the marks aren’t fixed in the same way the DNA sequence is: some of them can change throughout your lifetime, and in response to outside influences. Some can even be inherited, just like some highlighting still shows up when text is photocopied.

Epigenetics and our experiences

Any outside stimulus that can be detected by the body has the potential to cause epigenetic modifications. It’s not yet clear exactly which exposures affect which epigenetic marks, nor what the mechanisms and downstream effects are, but there are a number of quite well characterized examples, from chemicals to lifestyle factors to lived experiences:

  • Bisphenol A (BPA) is an additive in some plastics that has been linked to cancer and other diseases and has already been removed from consumer products in some countries. BPA seems to exert its effects through a number of mechanisms, including epigenetic modification.
  • The beneficial effects of exercise have been known for generations, but the mechanisms are still surprisingly hazy. However, there’s mounting evidence that changes to the pattern of epigenetic marks in muscle and fatty tissue are involved.
  • Childhood abuse and other forms of early trauma also seem toaffect DNA methylation patterns, which may help to explain the poor health that many victims of such abuse face throughout adulthood.

Epigenetic inheritance

This is an area where the hype has advanced faster and further than the actual science. There have been some fascinating early studies on the inheritance of epigenetic marks, but most of the strongest evidence so far comes from research done on mice. There have been hints that some of these findings also apply to human inheritance, but we’ve only just started to untangle this phenomenon.

  • We’ve known for some time that certain environmental factors experienced by adult mice can be passed on to their offspring via epigenetic mechanisms. The best example is a gene called agouti, which is methylated in normal brown mice. However, mice with an unmethylated agouti gene are yellow and obese, despite beinggenetically essentially identical to their skinny brown relatives. Altering the pregnant mother’s diet can modify the ratio of brown to yellow offspring: folic acid results in more brown pups, while BPAresults in more yellow pups.
  • Research on the epigenetic inheritance of addictive behavior is less advanced, but does look quite promising. Studies in rats recently demonstrated that exposure to THC (the active compound in cannabis) during adolescence can prime future offspring to display signs of predisposition to heroin addiction.
  • Studies of humans whose ancestors survived through periods ofstarvation in Sweden and the Netherlands suggest that the effects of famine on epigenetics and health can pass through at least three generations. Nutrient deprivation in a recent ancestor seems to prime the body for diabetes and cardiovascular problems, a response that may have evolved to mitigate the effects of any future famines in the same geographic area.

“More research is needed”

Epigenetics research continues apace in labs investigating a dazzling variety of topics. One interesting direction is the application of high-throughput sequencing technologies to the characterization of hundreds of ‘epigenomes’ (epigenetic marks across the entire genome). I manage a project that’s part of the International Human Epigenomics Consortium (IHEC), and am also a member of a couple of the consortium’s working groups, so I see for myself every day how fast this field is progressing. The goal of IHEC is to generate at least 1,000 publicly available ‘reference’ epigenomes (patterns of DNA methylation, six histone modifications, and gene activation) from various normal and diseased cell types. These references will serve as a baseline in other studies, in the same way that the original human genome project sequenced a reference genome to which scientists can now compare their own results to identify changes associated with specific diseases.

This is a field that’s guaranteed to keep generating headlines and catching the public’s interest. The apparent ability of epigenetics to fill some pretty diverse gaps in our understanding of human health and disease, and to provide scientific mechanisms for so many of our lived experiences, makes it very compelling, but we do need to be careful not to over-interpret the evidence we’ve collected so far. And we certainly need to be highly sceptical of anyone claiming that we can consciously change our epigenomes in specific ways through the power of thought.

Now that I’ve piqued your interest in this fascinating field (and maybe that of your unborn children. Epigenetics!), in my next piece I’ll explore the role of epigenetic changes in the onset of cancer and other diseases, and what this means for the development of new treatment options.

There are links to videos and other resources about epigenetics on the IHEC website. There’s also a free Massive Open Online Course (MOOC) in epigenetics offered by the University of Melbourne on the Coursera site; I just started the April 2014 session so I can vet it for work-related purposes and it’s great so far, although a pretty solid background in genetics is required.

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Posted by on 2014/05/04 in epigenetics, genetics


Quora activity for April 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!


How has smoking been proven to cause cancer?

Could intentionally causing cancer cells to mutate into a form more vulnerable help destroy cancers?

Can cancer be caused by defects in RNA splicing?

Why is breast cancer so deadly even after someone has been declared cancer-free for many years (i.e. it often comes back and is often deadly)?

How likely is “the cocktail effect” to be the reason for the increasing rates of cancer?

Other Scientific Subjects

How does mRNA decide which gene is dominant?

Geneticists, what are your feelings about the studies on epigenetics? I found a few who are vehemently opposed to its legitimacy, and I want to know if that’s common or exceptional.

Has anyone ever tried crossing animals with plants?

If the surface of our bodies were covered in photosynthetic cells, how much exposure to the sun would you need to sustain the body’s metabolic process?

Is there such a thing as an ideal human or organism?

What is a plasmid?

Science Books: Could you help me to find “scientific novels” in English or Spanish? Not “science fiction novels”, but stories about the human feelings of the people who deal with science.

Is Mary Roach a good science writer?

About Scientific Research and Careers

What great prank has a scientist pulled on his or her colleagues?

What determines a reasonable budget for a research grant?

How many projects is a PhD student supposed to lead and do by him/herself?

Who should not try to become a professor?

What are you doing with your life science PhD? How did you get there? Why did you choose it?

To what extent is/was your choice to pursue a career in academia influenced by things other than interest in a subject?


What is the best Schrödinger’s Cat joke? (featuring my favourite photo of my cats – Saba (on the left of the photo) and Google)

What are some witty and amusing things you have heard on an airplane?

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Posted by on 2014/05/04 in Quora


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 🙂


Quora activity for March 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!


What are driver and passenger mutations in the context of cancer cells/genomes?

Why isn’t there more research on why most people never get cancer even if they smoke or are exposed to some other carcinogen?

What is mutational heterogeneity?

Other Scientific Subjects

What is epigenetics, in layman’s terms? (my answer was featured on the official Quora Twitter account!)

DNA: Is the amount and type of information in an individual’s DNA the same on the day they are born as on the day they die?

What is your favourite science book?

About Scientific Research

Academia: Do some professors prefer graduate students who don’t have the same exact research interests as them?

Is there a list of all major scientific research funding bodies?


Why would you live in a country with dark, cold,  wet, or snowy winters when you could live one with warmth and sun all year-round?

Book Recommendations: What is your favourite Canadian book?


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Posted by on 2014/04/13 in Quora


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: 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?


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


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.