Genetic Roulette in a New World

In 2003 it was a sensation. No really – it’s probably true that in medicine only the first human heart transplant operation back in 1967 has generated as much publicity. That was in the pre-web dark age but, nevertheless, the South African surgeon Christiaan Barnard was immortalized as a global hero: even the patient’s name was on everyone’s lips (Louis Washkansky if you’re struggling to recall) and you can re-live the whole event at the Groote Schuur Hospital museum in Capetown. But, although 2003 was just a decade ago, in today’s world sensations fade almost with the following dawn, whether they are pop groups or life-changing scientific advances.

So if now you mention “The Human Genome Project” to a man on the Clapham omnibus you are likely to elicit only a puzzled look. What happened in 2003 was of course that the genetic code – that is the sequence of bases in DNA – was revealed for the entire human genome. And an astonishing triumph it was, not least because, in contrast to almost everything else in history with a major British component, it was completed within schedule and under cost.

The feat was deservedly greeted with a fanfare of public interest unprecedented for any scientific project short of the early space missions. President Clinton in the White House was hooked-up live to whoever was living in No. 10 at the time, the leading British scientists in this amazing project dropped in for tea and Mike Dexter, then Chairman of The Wellcome Trust and a restrained and conservative fellow – being a scientist – described it somewhat inelegantly as “… the outstanding achievement not only of our lifetime, but in terms of human history.”

The Sanger Centre, Cambridge

The Genome Analysis Centre, Norwich

The Genome Institute at Washington University

However, even more remarkable is what happened next. The ensuing decade has brought technical advances so breathtaking as to almost overshadow the original human genome project itself. This quite staggering revolution has seen the introduction of fully automated, high throughput flow cells that simultaneously carry out hundreds of millions of separate sequencing reactions – just say that slowly. In the jargon it’s called ‘massively parallel sequencing’. The upshot of this stunning technology is that sequencing speed has gone up by 100 million times whilst, almost unbelievably, the cost has dropped by a factor of 10,000. Even computing science can’t match that progress!

One consequence of this incredible, though relatively unpublicised, revolution is that genomes can be now be sequenced on an industrial scale and in the years to come that is going to impact on every facet of mankind’s existence. Thus far the field of cancer has been the foremost recipient of this technological broadside with thousands of tumour genomes now sequenced. This has unveiled the almost incomprehensible panoply of genetic changes that cells can sustain and yet emerge still capable of proliferating. One of the first cancer genomes to be sequenced was that of a female who had died from leukemia. The work was carried out by The Genome Institute at Washington University in St. Louis, Missouri and since then, under its Director Richard Wilson, this group has continued to be a world leader in genomics and in particular in unravelling the extraordinary complexity of the group of cancers collectively called leukemias.

Wilson and his colleagues know, of course, that they are at the forefront of the most extraordinary transformation in medicine – because eventually it will affect everyone –though Rick Wilson himself is as improbable a revolutionary as you could imagine: a gentle, soft-spoken American, he’s what on this side of the pond would be called a thoroughly nice chap.

However, if they had any doubts about the direction in which their science was leading the world, these would have been dispelled when one of their own community, Lukas Wartman, was diagnosed with a very rare form of leukemia. This had first appeared ten years ago when Lukas was a student completing his medical degree at Washington University, and at that time it had been treated with chemotherapy and a bone-marrow transplant.

In the following years, Dr. Wartman had pursued his career goal of becoming a practicing oncologist specializing in leukemia until, in July 2011 the disease returned and he went into relapse. As his condition deteriorated rapidly and only one outcome seemed possible, those treating him turned in desperation from conventional approaches to local expertise. They applied genomic analysis to his cancer cells. From the vast number of disruptions identified, one in particular stood out: an abnormally expressed gene that had previously been associated with other types of leukemia but is very rare in the form Wartman had developed.

By an unlikely chance there is a drug available that can knock out the activity of the protein made by that gene. Its effect was phenomenal, restoring the normal blood count and achieving complete remission. This wonderful outcome does not mean that Dr. Wartman is cured for life – but for now he is alive and well – and a co-author of the group’s latest paper – on leukemia.

He had been a desperately unlucky in that the genetic roulette that is life generated in him a hand of mutations that drove the development of a rare and almost invariably lethal form of leukemia. But life also smiled on Lukas Wartman in that circumstances found him at the heart of the genomics revolution that is ushering in a new world of medicine. His isn’t the first life to be saved through the use of this fabulous technology but he is one of the first few who will, in years to come, be followed by many as these marvellous methods for diagnosis and the design of treatment come into widespread use.

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A Ray of Sunshine

One of the fascinating things about cancer is that it touches every aspect of biology. Of course, most will know that it’s caused by mutations – changes in the material that carries our genetic code. But many influences play on the genetic keyboard of DNA and those that are part of the world around us are a very mixed bunch. In Betrayed by Nature I split them into two: those we can do something about and the rest. The latter includes radiation from the ground… it’s all around us, we’ve evolved bathed in it and, apart from not living where the levels of radon are particularly high, there’s nothing we can do about it – so just forget it.

At the other end of the spectrum, so to speak, comes sunshine. We’ve evolved with that too – indeed we wouldn’t be here without it. Aside from driving photosynthesis in plants, humans use the radiant energy of the sun to make vitamin D (sometimes called the “sunshine vitamin”). Vitamin D deficiency is one cause of the childhood bone defect rickets, a condition that has reappeared in the UK in recent years because some kids are seeing less of the sun. So for humans catching the rays is desirable but we teeter along a sunny tightrope between what we need and what may ultimately be fatal. The risk comes from the ultra violet component of sunlight – radiation that has sufficient energy to damage DNA directly, making it a mutagen that can cause cancer. The cancer in question is, of course, melanoma that develops from abnormal moles on the skin. The global incidence of melanoma is increasing and, in the UK, about 90% of cases are estimated to be linked to exposure to ultra violet light. To most folk this means sunshine but those so inclined can walk the tightrope horizontally by using sunbeds (incredibly, in 1999 Cancer Research UK found that a quarter of men and a third of women questioned said they’d used a gizmo of this sort in the previous six months).

Which goes to show that human beings seem unable to resist the pursuit of the unattainable. The fair skinned think it cool to be darker whilst pharmaceutical giants are apparently making pots from selling creams to Indian ladies on the pitch that they will lighten their skin!

… and not so good

Good rays …

With a sigh for humanity let us pass from risks we take for no reason other than vanity or stupidity to those we may feel obliged to take as the lesser of two awkward options. There’s almost no chance that anyone reading this hasn’t had an X-ray of some sort. We have them to give our dentist a precise guide to the cause of our agony, rather than have him solve the problem by a series of trial and error excavations, or to tell our orthopaedic surgeon how best to go about piecing together the results of our latest stress-test on the human frame. We know X-rays are bad for us – they’re even more energetic than ultra violet radiation, so they’re a super-mutagen. Waves of cancer you might say.

So the issue here is one of choice. It’s a bit like a general anaesthetic: they do tend to make you throw up and about one in every 100,000 is fatal but, confronted with surgery, which would you vote for: a whiff of halothane or the offer of a slug of whisky and a rag to bite on? Computed tomography (CT) is an alternative application of X-rays but, instead of a single shot giving a two-dimensional image, CT acquires a large number of such images, taken as the radiation beam moves through the body, to give a 3-D picture. This can represent whole organs, and it has become an immensely powerful diagnostic tool since its introduction in the early 1970s. However, there’s no advance without anguish, and the additional information provided by a CT scan requires much more radiation than a traditional X-ray (typically 10 millisievert (mSv) compared with about 0.04 mSv for a chest X-ray). As our annual dose of “unavoidable” natural radiation is about 3 mSv it’s probably safe to say that these medical exposures are not a serious hazard – although babies in the womb are particularly sensitive to radiation. Even so, there are estimates that about 1% of USA cancers are due to CT scans, although there is no evidence that doses below 100 mSv induce tumours in animals.

A new study has enlarged the picture by finding that CT scans of children under 15 may increase the risk of leukemia and brain cancer. Three-fold increases were estimated for acute lymphoblastic leukaemia as a result of five to ten scans and for brain tumours by two or three scans. This sounds somewhat scary but it’s worth noting that these diseases are very rare in children. In the UK the incidence in under-20 year olds is just over four per 100,000 of leukemia – slightly less for brain or central nervous system cancers.

So the evidence indicates a small increase in an already low level of risk. As ever in life, therefore, it’s a matter of balance. The sensible advice for children (and everyone else for that matter) is not to have CT scans unless they are likely to provide critical clinical information that cannot be obtained by other means, for example, ultrasound or conventional X-rays.

Reference

Pearce, M.S., Salotti, J.A., Little, M.P., McHugh, K., Lee, C., Kim, K.P., Howe, N.L., Ronckers, C.M., Rajaraman, P., Craft, A.W., Parker, L. and de González, A.B. (2012). Radiation exposure from CT scans in childhood and subsequent risk of leukaemia and brain tumours: a retrospective cohort study. The Lancet 380, 499–505.