Powdering Your Nose and Other Parts

If you were asked ‘What is the worst thing about being a research scientist?’ you might well come up with ‘Feeling stupid every day’ – especially if you’d read Martin Schwartz’s wonderfully funny and incisive essay ‘The importance of stupidity in scientific research’ pointing out that research means battling with the unknown. Bad though that is, I can tell you, on the basis of collecting absolutely no data whatsoever, that 100% of scientists would answer ‘Literature’ – or to be slightly more expansive ‘Keeping up with published research.’ To give the rest of mankind a feel for their problem, suppose you work on a gene called MYC which is one of the most powerful cancer drivers: the Web of Knowledge database lists 3,839 hits for MYC as a topic and 468 with it in the title (which means you really ought to read those papers!). So far this year! That’s six months  worth!!

Dusting down the literature

Broadly speaking, scientific literature comes in two categories: a huge one that you might call worthy but dull and a tiny one to which you ought to say ‘Wow!’, that is, there’s some amazing revelation about the way life works, a brilliantly clever method or some stunning insight. But there are two other small classes of which we rarely speak. One is, of course, stuff that is poor (or worse still plagiarized) and should never have been published. The other is perfectly OK – indeed you might even say ‘good someone’s done it’ – it’s just that your heart sinks when you see the title because you know what’s in store.

talc-powder

My latest heart-sinker is a zippy little thing called Genital powder use and risk of ovarian cancer: a pooled analysis of 8,525 cases and 9,859 controls and it has that effect because the title tells all. They’ve tackled a question that’s been around for 30 years, namely whether applying talcum powder to the nether regions can cause cancer of the ovaries, by pulling together data from separate studies with mixed conclusions, so that a kind of average emerged from the haze as a modest increased risk.’

What’s my problem?

Being certain that such a title will be picked up by the press and reported in a misleading and over-hyped fashion. Step forward the MailOnline (Women who regularly use talcum powder to keep fresh raise their risk of ovarian cancer by almost a quarter SHOCK HORROR!!). OK, I added the last two words but they were there by implication. It has to be admitted that the scientists didn’t help by calculating Odds Ratios (the ratio of the odds of an event occurring in one group to the odds of it occurring in another group), with the inevitable result that they were interpreted as ratios of risks, which overestimates the effect. However, if journalists actually bothered to read the papers they latch on to, it might occur to them that a balanced picture might be conveyed by quoting what the scientists themselves said. In this case the odds ratio was 1.24 which they summarized as ‘Genital powder use was associated with a modest increased risk of epithelial ovarian cancer.’ It would also help the non-scientist reader to put things into context by, in this case, noting that for ovarian cancer the average lifetime risk is about 1.4%. Thus even if you did have an increase of one quarter, the risk is still less than 1.8%.

The ordinary reader might also appreciate a comment on some of the problems faced by such studies. Not the least of these is that they are retrospective (i.e. they asked folk to recall what they used, when and how). It’s not difficult to be skeptical about the precision of the responses, especially when you’re tiptoeing around in what might be called delicate areas, and that’s before you mention the different wording in each study of questions that were pretty convoluted anyway. It’s also worth noting that the analysis showed no increase in risk with prolonged use, which is a little odd (recall that for smoking the more you do it the higher your chances of lung cancer).

Anything else worth adding?

Talcum powder, for this is what we’re talking about, is made from talc which is mostly magnesium, silicon and oxygen and the powder is, of course, widely used because it absorbs moisture and reduces friction, helping to keep skin dry and rash-free. Asbestos, another silicate, occurs together with talc in nature, and it causes the form of lung cancer called mesothelioma. Before 1976, talcum powder was commonly contaminated with asbestos but since the 1970s talcum products have been asbestos-free. There is evidence both in humans and rodents that talc particles can travel up through the genital tract and alight on the surface of the ovaries. Such particles can cause inflammation, one way in which cancer development can be set off, but there is no evidence that talc does promote ovarian cancer in this way.

Ideally in looking for cause and effect, scientists like to get a handle on mechanism. Somewhat surprisingly, for an effect that is modest at most, there is the glimmering of a lead. It comes in the form of a family of enzymes that can detoxify carcinogens (they’re glutathione S-transferases) but the genes encoding two of them, GSTM1 and GSTT1, are missing in about 50% and 20% of Caucasians respectively – so, of course, their activity is lost. There is one study showing that women with GSTM1-present and GSTT1-missing have a stronger association between talc use and ovarian cancer risk. The number of cases is small and it is possible that the effect is not real. It’s also not at all clear how the actions of this combo might interact with the effects of talc. Nevertheless, it is striking that it’s the only pairing of these two genes that shows an association.

What’s a girl to do?

1. Don’t read anything by a journalist that talks about Odds Ratios because the odds are they won’t have a clue what they’re on about.

2. Do read Thou Shalt Not Report Odds Ratios’, Mark Liberman’s witty but brutal evisceration of two ‘science editors’, Mark Henderson of the London Times and Steve Connor of the Independent newspaper.

3. Note that the authors of this study say that genital powder exposure is associated with a ‘small-to-moderate increased risk.’ – nothing stronger than that.

4. Remember that there’s no evidence that talcum powder applied anywhere other than the genital area can cause any problems and that includes the lungs. Even rats forced to inhale talc for 6 hours a day, five days a week for over two years were reluctant to get lung cancer although the incidence did increase in females (maybe they were just trying to escape the Dickensian smog ‘Strewth guvnor, I ’ardly get to see the nippers these days: may as well end it all by getting lung cancer’).

5. Bear in mind that the International Agency for Research on Cancer (IARC) classifies talc-based body powder as a class 2b carcinogen “possibly carcinogenic to human beings.”

6. Be aware that the major factors increasing the risk of ovarian cancer are (1) increasing age, (2) family history of breast or ovarian cancer, (3) being overweight and (4) hormone replacement therapy, whilst having children and breastfeeding them as well as taking the pill reduce the risk.

7. Finally, if the possibility of a slight increase in a small risk really spooks you, avoid orifice powdering and let nature take care of things. Or, if you’re really desperate for friction-free movement, use cornstarch powder: it’s a carbohydrate and there’s absolutely no evidence that it is a risk factor for ovarian cancer.

References

Terry, K.L., Karageorgi, S., Shvetsov, Y.B. et al. (2013). Genital powder use and risk of ovarian cancer: a pooled analysis of 8,525 cases and 9,859 controls. Cancer Prevention Research Published OnlineFirst June 12, 2013.

http://www.dailymail.co.uk/health/article-2343974/Women-regularly-use-talcum-powder-increase-risk-ovarian-cancer-24.html

Gates, M.A., Tworoger, S.S., Terry, K.L. et al. (2008). Talc use, variants of the GSTM1, GSTT1, and NAT2 genes, and risk of epithelial ovarian cancer. Cancer Epidemiology Biomarkers & Prevention 17, 2436-2444.

http://itre.cis.upenn.edu/~myl/languagelog/archives/004767.html

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Signs of Resistance

In Beware of Greeks … we noted that in one sort of leukemia at least, tumour cells have come up with an extraordinary way of escaping from the bone marrow where they start life into the circulation where they cause trouble – by releasing pieces of their own DNA that then break down the retaining barrier.

Keeping track of tumors

Curious behaviour though it may be, there’s nothing new about the idea of cells shedding bits of their genetic code – that was first shown to happen over 60 years ago. What is novel is the evidence that not only does this happen in a variety of cancer cells but that modern methods enable those fragments to be isolated from just a teaspoonful of blood: the sequence of the DNA can then be determined – which gives the mutational signature of the original tumour. A remarkable development has now shown that repeating these steps over a period of time can reveal the response of secondary tumours (metastases) to drug treatment (chemotherapy).

Untitled

One great advantage of this blood sampling method is that it is as near as makes no difference ‘non-invasive’. That is, it uses only a (small) blood sample and there’s no need for painful excavations to dig out tumour samples. The study, largely funded by Cancer Research UK, looked at three major cancers (breast, ovarian and lung) and identified specific mutations caused by drugs over a period of one to two years. For good measure they also took tumour samples to show that the mutation patterns found in circulating DNA did indeed represent what had gone on in the tumour itself. In other words, they had established what scientists like to call ‘proof of principle’ – i.e. we can do it!

There’s another more subtle advantage of this approach in that it gets round a problem we described in Molecular Mosaics: tumours are a mixture and the mutational signature differs depending on which bit you sample and sequence. The cell-free DNA fragments collected from blood are a gemisch – an averaged signature if you like – that may therefore give a better picture of the target for drug cocktails at any given time during tumour evolution.

Why is this so important?

There are two main reasons why it’s difficult to exaggerate the potential important of this step. The first is that metastasis accounts for over 90% of cancer deaths, the second that the fiendish ingenuity with which tumours negate chemotherapy, i.e. develop drug resistance, is one of the biggest challenges to successful treatment. So, the sooner changes that enable tumours to become insensitive to drugs can be detected the better in terms of adjusting the treatment regime. Even more exciting, however, is that notion that the DNA shed by cancers into the circulation may permit detection years or even decades earlier than is possible with any of the current methods (e.g., mammography) – with screening being carried put routinely from blood samples. Being even more optimistic, very early stage tumours may be particularly susceptible to appropriate drug combos, so that we might look forward to the day when chemotherapy replaces surgery as the first line of treatment for most cancers.

Reference

Murtaza, M. et al., (2013). Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature 497, 108–112.

Policing DNA

In A Sinister Side to Sequencing we noted that, wondrous though the advances in sequencing DNA have been, every silver lining …, so to speak. This was in the context of our now being able to determine whether babies will be born with genetic defects, raising the prospect that parents may opt not to have afflicted children. Because we feel that the avoidance of politics has such beneficial effects on the tone of these pieces, we did not mention another problem raised by the ready availability and sophistication of current DNA analysis methods, namely use of the data by police forces, specifically by the procedure usually called DNA fingerprinting. But, needs must …

First of all, what’s DNA fingerprinting?

DNA profiling (or fingerprinting) methods, pioneered by Sir Alec Jeffreys at the University of Leicester, have undergone substantial refinement since they were first used as a police forensic test in 1986 to identify the rapist and killer of two teenagers. Regardless of detail, the essential point is that that the genetic code of individuals is compared using DNA that can be extracted from most tissues or body fluids (e.g., blood, semen, cheek cells, etc.). From the samples to be compared short lengths of DNA are generated and separated by size in a gel, stained so that the DNA fragments show up as bands. Each of us has a unique pattern. In the picture the pattern from suspect 2 is identical to that of DNA taken from the crime scene – so he dunnit!

DNA patterns

 

 

 

Short lengths of DNA samples obtained from a crime scene and from the tissues of three suspects separated in a gel and stained to show as black bands

 

 

 

 

Why is it in the news?

The Supreme Court of the United States has just ruled that the police should be permitted to take DNA samples from an arrested individual, as Maryland officers had done from a character who’d been waving a shotgun only to find that he’d committed an unsolved rape case in 2003 from which they were still holding a DNA sample. An excellent result, you might think. Perhaps, but the ruling has nevertheless got the liberals up in arms, as represented by Antonin Scalia, an Associate Justice of the Supreme Court. Put briefly, his point is that DNA sampling is following the path of fingerprinting, things will go headlong downhill and before long we’ll have to submit to it if we want to get on a plane or play for a school sports team. This would clearly be an unacceptable invasion and so, inevitably, The Fourth Amendment to the United States Constitution is invoked – for outsiders that’s the thing purporting to protect citizens from ‘unreasonable’ actions by the powers that be, whatever that means to any administration that happens to be in charge.

No one sane is arguing that the police should not be permitted to use DNA in the pursuit of villains. The problem is how to keep the lid on Pandora’s box. So, without for a moment implying that the good denizens of the US of A might be a touch parochial, let’s take the drastic step of casting a glance beyond the limits of sea to shining sea.

In the rest of the world?

What better place to start than with the mother of modern democracy and what was the land of the free before the US of A was invented? Shock horror: it emerges that little old England has more DNA samples per head of population in the hands of its police than any other country for which information is available! How can this have come about? Well, the Police and Criminal Evidence Act of 1984 permitted the police to take fingerprints and body samples without consent from people charged with, or convicted of, a recordable offence (these include begging, being drunk and disorderly and taking part in an illegal demonstration – ‘illegal’ having been interpreted somewhat flexibly in recent times). However, those powers were extended in 2004 to permit samples being taken from anyone arrested on suspicion of any recordable offence. You will recall that this was during the Premiership of Mr. Blair, a chap with little interest in civil liberties and none at all in parliamentary democracy.

Back in 1949, when a parliamentary democracy seemed an immovable feature of British life, the United Kingdom (UK) became a founder member of something called The Council of Europe – designed to promote cooperation over matters relating to the law and human rights. Bear in mind that this is quite distinct from the European Union (EU) – the organization that lives in decadent style in Brussels to which the mother of parliaments has for some time ceded control of its affairs. EU members include Poland, Hungary and Estonia and it’s largely run by the Germans and the French. Funny how things turn out. Shock horror number 2 is that the UK is the only Council of Europe member that allows retention of biological samples from people who have been acquitted of charges or against whom criminal charges have been dropped. The Council of Europe has a sort of sub-body called The European Court of Human Rights before which was recently brought a UK case about whether the retention of DNA and fingerprints from innocent people is consistent with human rights law. In short, they don’t think it is and it’s worth quoting a key phrase in their conclusions: “… retention … constitutes a disproportionate interference with the applicants’ right to respect for private life and cannot be regarded as necessary in a democratic society.

So, what’s happened?

Well, for once let us rejoice in being interfered with by those pesky Europeans because, as of May 2012, the UK now has a Protection of Freedoms Act covering the operation of the UK Police National DNA Database. A critical feature is that DNA and fingerprint records of over a million innocent individuals will be deleted and the DNA samples destroyed. It should be added that seemingly Maryland law also requires destruction of DNA samples taken in cases that do not lead to conviction.

What will be done?

The problem with protecting freedoms is that laws are OK but someone needs to do the protecting. No one who has reviewed the activities of the British police that have come to public attention over the last twenty years would have any confidence either in their morality or their competence, never mind their inclination to police themselves. The fact that, according to GeneWatch UK, companies have been permitted to use the police DNA Database for research purposes without, of course, individual consent would confirm your doubts.

Re-crossing the Atlantic it would also seem sensible to ensure first that reasonable legal safeguards are in place across all states to control police activity  but after that to keep Mr. Scalia’s concerns in mind and remain vigilant in ensuring that those provisions are adhered to.

Finally, all that having been said and with due regard to the seriousness of this matter, one might observe that countries prone to promoting themselves as models of human rights that nevertheless pass laws permitting indefinite detention of citizens without trial and are not averse to the use of torture have somewhat weightier matters to resolve than what the fuzz do with a few cheek swabs.

References

https://cancerforall.wordpress.com/2012/07/01/a-sinister-side-to-sequencing/

http://www.thedailybeast.com/articles/2013/06/04/big-brother-invades-your-genes.html

http://www.genewatch.org/sub-539478

National Defense Authorization Act, 2012.