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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