Seeing a New World

May I wish readers a Happy New Year – and indeed extend my felicitations to non-readers with the hope that they too will become followers! What a good idea! Not least because I suspect many are viewing the new year with a mixture of anxiety and despair. But I can promise there’s nothing like the sanity of science to restore you after a few minutes contemplating how we’re doing on the economic and political fronts.

Your starter for 2017

By happy chance a few weeks ago I tried to explain how it’s now possible to ‘re-write the manual of life’ – that is, to engineer our DNA, to fix broken genes if you like. This means that, in theory, it’s possible to correct errors in our genetic code that cause genetic diseases. As there are over 6,000 of these and they include Down syndrome, cystic fibrosis and Alzheimer’s disease, there’s no need to say it’s important. There are several ways of going about this but the one I described is called CRISPR and it’s had a lot of media coverage.

Right on cue

Well done then Keiichiro Suzuki, Juan Carlos Belmonte and friends from the Salk Institute in California together with colleagues from other centres in Spain, Saudi Arabia and China for their December paper describing a new CRISPR twist. They used a rat model of retinitis pigmentosa, a genetic disease that is a major cause of inherited blindness, afflicting about one and a half million people worldwide (one in 4,000 in the UK).

The CRISPR-Cas9 system is great but it works best in dividing cells (e.g., in skin and gut that are renewing all the time) and it’s particularly useful for knocking out genes rather than inserting new DNA. The latest modification allows a new gene to be inserted into a specific site in the DNA of cells that are not dividing (e.g., those of the eye or brain).

The bits of CRISPR-Cas9, which insert DNA at very precise locations within the genome, are delivered to target cells as part of an inert virus. However, the package also includes DNA that encourages the cells to use a repair process that can be turned on even in non-dividing cells. So CRISPR-Cas9 cuts the cell’s DNA at an exact sequence and the cell then repairs the double-strand breaks (by a process called non-homologous end joining (NHEJ) that glues the broken ends directly together). Give the cell a new bit of DNA (e.g., your favorite gene) and that will get patched in – bear in mind that the cell doesn’t ‘know’ what it’s doing: it just tries to fix damaged DNA with whatever’s at hand.

And the target?

Retinitis pigmentosa occurs when a chunk of a gene called Mertk is lost. After quite a lot of experiments to show that their method worked, Suzuki, Belmonte & Co made a viral carrier that included a normal Mertk gene and injected it under the retina of rats with the disease. After about 5 weeks the rats were making Mertk RNA as a result of the gene being correctly ‘knocked-in’ to eye cells. The light-detecting region of the eye, greatly reduced by the disease, was significantly restored, with associated appearance of MERTK protein.

      Diseased    Normal     Treated                         Diseased         Normal         Treated

pic

Left trio: Sections of the light-detecting layers of the eye in diseased (left), normal (centre) and diseased post-treatment rats (right). Right trio: corresponding fluorescence images showing MERTK expression (red: highlighted by white arrows); Cells labeled blue. (Suzuki et al. Nature 1–6 (2016) doi:10.1038/nature20565)

How did the rats see it?

Well, after treatment they were able to detect light and had significantly recovered their visual functions, albeit not to completely normal levels.

The usual caveats apply: the method isn’t hyper-efficient and a human treatment is still a long way off. Nevertheless, it’s a significant step.

The same group has also shown, using a way of re-programming the expression of just four genes, that it’s possible to arrest the signs of ageing. In other words, in mice this time, tinkering with these genes can increase lifespan – and yes, we have versions of these genes and in us they also control cell renewal.

So the New Year message is clear to see. If we can avoid turning the planet into a desert or blowing ourselves to smithereens the future is really rosy – and maybe even infinite!

References

Suzuki, K. et al. (2016). In vivo genome editing via CRISPR/Cas9 mediated homology-independent targeted integration. Nature 540, 144-149.

Ocampo, A. et al. (2016). In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming. Cell 167, 1719–1733.

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A Sinister Side to Sequencing

As a youngster I naturally imbibed everything I was taught about sex. By the time I emerged from the British university system this amounted to precisely two things: babies come from ladies and there is a really exciting moment just after one pops out when somebody says “It’s a boy!” or, as a variant, “Congratulations Mrs. Miggins, you have a lovely daughter!”

 

Many years and a career in science later, I now know a little more including the fact that out of every 100 babies born one will have an error in their genetic material that will give rise to a disease. There are more than 3,000 of these diseases, each caused by mutation of a single gene. For some only one of the two copies of a gene need be mutated: for others both copies must be abnormal for the disease to show itself, an example of the latter being cystic fibrosis that occurs in 1 in 2,000 of live births.

Many of these conditions are life threatening and those who have followed my recent eulogies about the wonders of DNA sequencing might have thought that a bit of its fire-power might be turned in their direction. Well, now it has been by a combination of several of the leading genetic disease groups in the USA. Their approach uses the fact that floating in the blood of pregnant women is a significant amount of DNA that has come from her developing baby. This can be easily isolated from a small blood sample (so the procedure is ‘non-invasive’). Repeated sequencing is then used to compare the entire DNA code from junior with that of both his Mum and Dad. This is essential to obtain the accuracy required for reliable detection of mutations carried by the fetus.

Hitherto it has been possible to detect conditions such as Down syndrome because that arises from a gross abnormality – an extra copy of an entire chromosome. However, this work means it is now feasible to do comprehensive, non-invasive, prenatal screening for all genetic disorders. The methods need to be refined and the cost lowered before this becomes generally available but you can be sure this will happen sooner rather than later. A by-product will, of course, be an accounting of X and Y chromosomes, but the suspense of that unknown has been long banished from delivery rooms with the coming ultrasound scans. It might also be noted that inherited mutations in major ‘cancer genes’ would also be picked up – though they contribute only about 10% of cancers.

Whilst this is yet another remarkable scientific advance that in due course will affect many lives, it comes with some serious strings attached. Knowing that an infant will be born with a given defect will mean that the best way of dealing with the condition can be planned in advance. However, it also means that parents may opt not to have afflicted children. This presents serious social and legal challenges that will be magnified if we begin to define genetic variants that associate with, say, intelligence, ball skills or whatever.

For neither the first nor the last time, the wonders of science present mankind with both riches and conundrums.

Reference

Kitzman, J.O., Snyder, M.W., Ventura, M., Lewis, A.P., Qiu, R., Simmons, L.E., Gammill, H.S., Rubens, C.E., Santillan, D.A., Murray, J.C., Tabor, H.K., Bamshad, M.J., Eichler, E.E. and Shendure, J. (2012). Noninvasive Whole-Genome Sequencing of a Human Fetus. Sci Transl Med 4, 137ra76 (2012); DOI: 10.1126/scitranslmed.3004323

http://www.nytimes.com/2012/06/07/health/tests-of-parents-are-used-to-map-genes-of-a-fetus.html?_r=1&pagewanted=all