Caveat Emptor

 

It must be unprecedented for publication of a scientific research paper to make a big impact on a significant sector of the stock market. But, in these days of ‘spin-off’ companies and the promise of unimaginable riches from the application of molecular biology to every facet of medicine and biology, perhaps it was only a matter of time. Well, the time came with a bang this June when the journal Nature Medicine published two papers from different groups describing essentially the same findings. Result: three companies (CRISPR Therapeutics, Editas Medicine and Intellia) lost about 10% of their stock market value.

I should say that a former student of mine, Anthony Davies, who runs the Californian company Dark Horse Consulting Inc., mentioned these papers to me before I’d spotted them.

What on earth had they found that so scared the punters?

Well, they’d looked in some detail at CRISPR/Cas9, a method for specifically altering genes within organisms (that we described in Re-writing the Manual of Life).

Over the last five years it’s become the most widely used form of gene editing (see, e.g., Seeing a New World and Making Movies in DNA) and, as one of the hottest potatoes in science, the subject of fierce feuding over legal rights, who did what and who’s going to get a Nobel Prize. Yes, scientists do squabbling as well as anyone when the stakes are high.

Nifty though CRISPR/Cas9 is, it has not worked well in stem cells — these are the cells that can keep on making more of themselves and can turn themselves in other types of cell (i.e., differentiate — which is why they’re sometimes called pluripotent stem cells). And that’s a bit of a stumbling block because, if you want to correct a genetic disease by replacing a defective gene with one that’s OK, stem cells are a very attractive target.

Robert Ihry and colleagues at the Novartis Institutes for Biomedical Research got over this problem by modifying the Cas9 DNA construct so that it was incorporated into over 80% of stem cells and, moreover, they could switch it on by the addition of a drug. Turning on the enzyme Cas9 to make double-strand breaks in DNA in such a high proportion of cells revealed very clearly that this killed most of them.

When cells start dying the prime suspect is always P53, a so-called tumour suppressor gene, switched on in response to DNA damage. The p53 protein can activate a programme of cell suicide if the DNA cannot be adequately repaired, thereby preventing the propagation of mutations and the development of cancer. Sure enough, Ihry et al. showed that in stem cells a single cut is enough to turn on P53 — in other words, these cells are extremely sensitive to DNA damage.

Gene editing by Cas9 turns on P53 expression. Left: control cells with no activation of double strand DNA breaks; right: P53 expression (green fluorescence) several days after switching on expression of the Cas9 enzyme. Scale bar = 100 micrometers. From Ihry et al., 2018.

In a corresponding study Emma Haapaniemi and colleagues from the Karolinska Institute and the University of Cambridge, using a different type of cell (a mutated line that keeps on proliferating), showed that blocking P53 (hence preventing the damage response) improves the efficiency of genome editing. Good if you want precision genome editing by risky as it leaves the cell vulnerable to tumour-promoting mutations.

Time to buy?!

As ever, “Let the buyer beware” and this certainly isn’t a suggestion that you get on the line to your stockbroker. These results may have hit share prices but they really aren’t a surprise. What would you expect when you charge uninvited into a cell with a molecular bomb — albeit one as smart as CRISPR/Cas9. The cell responds to the DNA damage as it’s evolved to do — and we’ve known for a long time that P53 activation is exquisitely sensitive: one double-strand break in DNA is enough to turn it on. If the damage can’t be repaired P53’s job is to drive the cell to suicide — a perfect system to prevent mutations accumulating that might lead to cancer. The high sensitivity of stem cells may have evolved because they can develop into every type of cell — thus any fault could be very serious for the organism.

It’s nearly 40 years since P53 was discovered but for all the effort (over 45,000 research papers with P53 in the title) we’re still remarkably ignorant of how this “Guardian of the Genome” really works. By comparison gene editing, and CRISPR/Cas9 in particular, is in its infancy. It’s a wonderful technique and it may yet be possible to get round the problem of the DNA damage response. It may even turn out that DNA can be edited without making double strand breaks.

So maybe don’t rush to buy gene therapy shares — or to sell them. As the Harvard geneticist George Church put it “The stock market isn’t a reflection of the future.” Mind you, as a founder of Editas Medicine he’d certainly hope not.

References

Ihry, R.J. et al. (2018). p53 inhibits CRISPR–Cas9 engineering in human pluripotent stem cells. Nature Medicine, 1–8.

Haapaniemi, E. et al. (2018). CRISPR–Cas9 genome editing induces a p53-mediated DNA damage response. Nature Medicine (2018) 11 June 2018.

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Twenty winks

Not now obviously but after you’ve read the first episode of this absorbing tale you may feel a nap is in order, despite the fact that in Wake up at the back we noted that snoring can give you cancer.

Setting aside that hazard, the general finding is that most people require seven or eight hours of sleep to function optimally. Fall short of that, to less than six hours even for one night, and we all know that the consequences may include a degree of grumpiness helped along by a tendency to clumsiness and generally heightened incompetence. If you happen to suffer from hypertension you could measure another result because your blood pressure will be even higher than usual for the rest of the day. However, these are all reversible states, so that real problems only come with more extended sleep deprivation and there is much evidence that this can profoundly affect memory, creativity and emotional stability, as well as leading to heart disease, diabetes and obesity. The molecular drive for the latter is that folk who are short of sleep have lower levels of the hormone leptin (which tells the brain you’ve had enough to eat) but higher levels of ghrelin (appetite stimulant). One week of only four hours nightly kip converts healthy young men to pre-diabetics in terms of their insulin and blood sugar levels.

The cancer link

To all of which must be added the dribble of reports over many years that disrupted sleep patterns, such as result from shift-work, may increase the risk of a variety of cancers (these include breast, prostate, bowel and endometrial cancers and also non-Hodgkin’s lymphoma). The effects are moderate (that is, the risk rise is small – typically up to 20%), making these findings suggestive rather than conclusive, although they are bolstered by a considerable number of studies on animals. So sleep, or rather lack of it, is yet another of these things that seems to affect cancer but for which really hard evidence is lacking. It’s not a9f5f190difficult to see why. You can’t put a number on ‘a good night’s sleep’ (though you can now get phone apps that record your every snort and contortion) nor do we understand the biological consequences of sleep disruption, and then there are the perpetual problems that everyone’s different and cancers take years to show themselves. However, you can put a figure on how you feel about sleep: our friends at the wonderful Karolinska Institute in Stockholm have come up with a Sleepiness Scale (1 = very alert, 9 = very sleepy, great effort to keep awake) – which could replace the traditional grunt when asked ‘How are you?’ ‘Oh, much as usual, about eight on the Karolinska Scale.’

Sleeping Off Breast Cancer

Trawling the literature it seems that the majority of cancer/sleep studies focus on the breast and a word about two of the most recent will suffice to paint the picture. In a large group of Japanese ladies over the age of 40 those who said they slept for less than six hours were markedly more likely to develop breast cancer than those who slept longer. Over nine hours a night (sleep that is) even appeared to give a degree of protection.

The main culprit for the breast cancer/sleep link is shift work, illustrated by the Danish military where women working night-shifts are more prone to breast cancer than those with normal sleep patterns and there is an upward trend in risk with years of night-shift work.

An association with ovarian cancer has also been reported although, somewhat perplexingly, that study didn’t show that the risk got bigger the longer night-shifts were worked. This rather confusing picture may reflect individual variation. As we all know, some folk are ‘larks’ – up at the crack of dawn – my lady wife is one – whereas others are ‘owls’ who perform better the later it is (no prize for guessing what kind of bird I am – bit of domestic incompatibility there!). It may be that ‘owls’ suffer less from night-shift perturbation and they may therefore be more likely to opt for that mode of work – and indeed the Danish study found that ‘larks’ on night-shifts were more likely to get breast cancer. As if that’s not enough, irregular shift patterns make it more difficult for women to conceive and working only nights increases the chances of miscarrying.

Similar results have been found for other cancers, notably of the bowel – 50% more likely to occur in those who sleep an average of less than six hours a night than those who zzzz for over seven. Put another way, the less than six hours risk is about the same as having a first degree relative with the disease or eating lots of red meat – and similar to that for breast cancer.

Mu Treadmill

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Mice Sleep Too

It’s not a bad idea to keep in mind that we are very similar to mice – we’ve got more or less the same number of genes and exercising (on a treadmill for example) helps to keep at least some cancers at bay. Another similarity is that sleep deprivation upsets the works so that, for example, in models of colon cancer it reverses the beneficial effects of moderate exercise.

So insomnia is no laughing matter, however it comes about, and next time we’ll put two and two together by looking at the molecular story – after which you really may need forty winks.

 References

Kakizaki, M. et al. (2008).  Sleep duration and the risk of breast cancer: the Ohsaki Cohort Study. Br J Cancer  99, 1502–1505.

Hansen, J. and Lassen, C.F. (2012). Nested case-control study of night shift work and breast cancer risk among women in the Danish military. Occup Environ Med., 69, 551–556.

Bhatti, P. et al. (2012). Nightshift work and risk of ovarian cancer. Occup Environ Med., 0:1–7. doi:10.1136/oemed-2012-101146.

Thompson, C.L. et al. (2011). Short Duration of Sleep Increases Risk of Colorectal Adenoma. Cancer 117, 841–847.

Zielinski, M.R. et al. (2012). Influence of chronic moderate sleep restriction and exercise on inflammation and carcinogenesis in mice. Brain, Behavior, and Immunity 26, 672–679.