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


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!


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.


Long-live the Revolutions!!




A little bit of what is now history …



Brings us to the present …







The prize … and the puzzle








A Refresher from the BBC

Regular readers will probably feel they know all this stuff but if you’re interested in a spirited and wide-ranging conversation about cancer with the wonderful Jeremy Vine on his BBC Radio 2 show yesterday you can find it at: about 1 hour 10 min from the beginning.

BBC Radio 4As ever, any arising thoughts, questions or comments appreciated – apart, of course, from the below the belt: “Judging by the photo it’s a good job it was radio not t.v.”


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.


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

Not getting cancer: a sequel to sequencing and evolution

The previous Kamilah the gorilla story leads us – where else – to the Naked Mole Rat. Addicted Naturists will have read last year that it too had been sequenced. Why on earth would they want the DNA code of the NMR? Maybe part of some fiendish chimeric cloning experiment inspired by The Wind in the Willows – these boffins need to get out more. But wait a minute! Despite the advances that mean genomes can be sequenced in a day, it’s still a complicated and expensive business – so there has to be a good reason for tackling another strain or species, as we saw with the gorillas. But what might that be for the humble NMR?

Water vole

Naked mole rat

It turns out that NMRs are far more astonishing chaps than even Kenneth Grahame could have imagined. In a way they’re rather well-named, being neither mole nor rat but a distinct species that diverged from rats and mice about 70 million years ago – much as the water vole (aka ‘Ratty’) is only distantly related to a true rat – and it parted company from us 20 million years earlier still. It’s a burrowing rodent so has to get by on low levels of oxygen, which it manages by having very small lungs and haemoglobin that is unusually efficient at picking up oxygen. When times get tough it can reduce its metabolic rate to a quarter of normal, its body temperature follows that of its surroundings, it doesn’t feel pain because its skin doesn’t make the required neurotransmitter, it lives in communes with a queen (the only one to reproduce – like some ants and bees) and it’s the longest-living rodent (over 30 years).

How amazing is that for a set of party pieces? But these stunning little tunnelers have one other trick that puts everything else in the shade. NMRs don’t get cancer. At least tumours have never been found in these fellers and if you take some of their cells, make them express a cancer-promoting gene and put them back into animals they still don’t form tumours – even though you get very aggressive growths if you do the same thing with mouse or rat cells.

What’s the secret of Naked Rats not getting cancer?

So what has the full DNA sequence of the NMR told us? Two genes have come to the fore that are very slightly altered compared with their human counterparts, and they’re of particular interest because we know they play major roles in protecting us – to the extent that they are knocked out in the majority of human cancers. What’s different in the NMR? Perhaps surprisingly, their variant genes make proteins that are just a little bit smaller than the human versions. Surprising because intuitively you might think that bigger would be better. However, proteins are almost incomprehensibly subtle creations – recall that changing just one amino acid out of 1480 in a protein made in the lung is enough to cause cystic fibrosis – and it may be that the slight changes in the DNA code do just enough to the shape of these proteins to make them ‘super’ protectors. The next step is to see what the NMR proteins do when they’re expressed in transgenic mice.

None of this means that the NMR is going to save mankind from one of its greatest scourges but it is encouraging that it has focussed attention on some of the key genes that stop us getting cancer. The other upshot is that it has reminded us how extraordinarily delicate is the balance in living things and how the slightest of changes in a protein can have immense effects.


Kim, E.B. et al. (2011). Genome sequencing reveals insights into physiology and longevity of the naked mole rat. Nature 479, 223–227.

The Creation of Cancer

Where do cancers come from?’ One of those dreaded childish questions – so best to get your thinking in first, rather than trying to answer on the hoof in the face of that unblinking stare of expectation. In the beginning, as you might say, we need a hand-wavy word on how DNA ‘makes proteins’, why they’re important (‘Proteins R Us’, in short) and what can go wrong with them.

DNA double-helix

The double helix of DNA

In 1953 Watson and Crick worked out the structure of DNA. It holds, of course, the secret of life and you might observe that it has the appropriate shape of a spiral staircase to nowhere. The ‘genetic code’ is the order of thousands of small bits that are linked together to make the very long molecules of DNA. These bits contain smaller bits called bases – four of them (A, C, G and T) – and they’re firmly stuck together so that each DNA molecule is pretty stable. In addition, bases in one DNA can stick to those in a second strand – hence the double-helix.


DNA encodes proteins

The essence of life is the transformation of the genetic code into the corresponding sequence of the building blocks that make proteins. The blocks are amino acids, stitched together to make proteins in much the same way as DNA is built from its base-containing units. There are 20 different types that can be glued together in any order, a typical protein containing a thousand amino acids. They tell the protein how to fold up into its final shape – a 3D structure unique for each protein. Many proteins are blobs (like balls of string) but, as you’d guess given that they do everything, they come in all shapes and sizes—cables, sheets, coils, bridges, etc. The idea then is fairly simple: flexible protein chains fold themselves into their working shape – and individual shapes enable proteins to do specific jobs. A simple sum can show that a limitless variety of proteins can be made: they are the machines of life that make all living things work and they have created all the species of life on earth.


Proteins make life possible because the exquisite choreography that generates their shape creates localised regions (sticky bits, clefts, cavities, etc.) for interactions with other molecules. These confer amazing versatility: proteins can ‘talk’ to each other and form relay teams that transmit information from one part of a cell to another, they can generate movement (as in muscles), and bring molecules together (e.g., when they act as enzymes driving chemical reactions that otherwise would not occur). But, as we all know, mistakes can happen even in the best-run enterprises. Mistakes in proteins arise from mutations – changes in the DNA code. Many diseases result from single base alterations: if that changes an amino acid the result can be a protein with dramatically altered function. A well-known example is cystic fibrosis: a protein made in the lung has one abnormal amino acid: the effect on its activity causes a build-up of mucus that makes breathing difficult and is a target for fatal infections.

Mutations and cancer

Cancers are also caused by mutations but they’re a bit more complicated, being driven by groups of mutations, rather than by one event. For most cancers these are picked up as we go through life – so the creation of a cancer is a slow process. Most don’t appear until we are over 60 years of age – collecting a suitable hand of mutations takes time. Because several critical mutations are required you’d guess that what tumour cells are up to is evolving a number of tactics for outsmarting their normal counterparts on the survival front. Indeed they are. They multiply in an unregulated way (because they ignore signals that control normal cells), side-step protective mechanisms that usually kill abnormal cells, divert nutrients from normal tissue to themselves, and make new blood vessels for the delivery of food and oxygen. Perhaps most amazingly of all, they seduce and subvert cells of the immune system: these begin by trying to eliminate the tumour but end up playing a key role in its growth – a sort of co-operative corruption.

All this is why cancer needs several mutations, and these are part of a wider genetic mayhem that will kill most cells – because essential survival genes are damaged. The cells that emerge as tumour precursors are molecular freaks in that they’ve both survived and picked up a bag of dirty tricks with which to out-compete their normal brethren. So, molecularly speaking, cancers are rare events. What’s more, there’s no forethought, no premeditation at work here. If the expression ‘unintelligent design’ conveys random chance in a game of genetic roulette then it’s an excellent descriptor of cancer evolution.

Stop me if you’ve heard it

If all this is beginning to sound familiar, so it should. It’s a completely undirected process that usually fails – but when it succeeds represents an extraordinary triumph of the flexibility of DNA and hence the adaptability of cells. Familiar, of course, because it’s a form of evolution that parallels the emergence of new species.

Tree of life

In the revolution started by unveiling the structure of DNA, the biggest advance has been finding a way to work out the order of bases – the genetic code. The first complete human DNA sequence came in 2003. Since then astonishing technical advances have led to thousands of tumours and hundreds of different species being sequenced. From this you can estimate when new species arose and draw a map of the evolution of all major forms of life on earth from a single, common ancestor. The time scale is incomprehensibly vast, but the picture is stunning in its simplicity, showing how everything is related – bugs, plants, fungi and humans – and how that family has emerged over nearly four billion years. This would have delighted Charles Darwin who, in 1859, was able to define evolution by natural selection only on the basis of what he could see. Molecular biology has now revealed its foundations.

Cancer evolution

In many ways tumours do indeed behave like new species: through the acquisition of mutations they out-compete normal neighbours and establish new niches in which to survive and prosper. But tumours are not new organisms: they’re normal cells that have gone off the rails – been hijacked, if you will, by delinquent genes. The big difference is the brief time scale over which tumours develop compared with the almost infinitely slow, step-wise testing of novel genetic variants in species evolution. So becoming a tumour is a very chancy business – but it’s a lot less fraught than making a new form of life. They take any short-term growth advantage conferred by a mutation without concern for the consequences.

Short trials and lots of errors

When a cell picks up its first growth-promoting mutation it has taken an irreversible step towards a life of crime. It’s become a high roller in the cellular casino, addicted to roulette of the Russian variety, and no amount of genetic counselling will reform it. If only it could think, how our tumour cell would long for a guiding hand – a more knowing form of life that could steer its orgies of DNA destruction toward survival. Alas! Like every other life form, tumours are in thrall to the random creator called chemistry. In a tiny few the dice fall favourably and they grow to rule their kingdom – briefly. Oh for an intelligent brain to design them not to kill their life-support system! Like cellular spaceships seeking immortality in the celestial wastes without the know-how to reach escape velocity, they can only burn brightly before crashing. Tumours are indeed a microcosm of evolution, working on an abbreviated time-scale – they’re dynamic Darwinism.