̽��ֱ�� of Cambridge - Robin Hesketh

Cambridge heads for Hay

jfp40 — Thu, 10 Apr 2014 09:20:09 +0000

̽��ֱ��Cambridge Series has been running for six years at the prestigious Festival and is part of the ̽��ֱ��’s commitment to public engagement. ̽��ֱ��Festival runs from 22nd May to 1st June and is now open for bookings.

This year's line-up includes Sir John Gurdon who was jointly awarded the Nobel Prize for Physiology or Medicine for the discovery that mature cells can be converted to stem cells. He will talk about his pioneering work on cloning.

Other speakers include Dr Ha-Joon Chang on economics, classicist Professor Paul Cartledge on after Thermopylae, Dame Barbara Stocking, former chief executive of Oxfam GB and president of Murray Edwards College, on the challenges for women in the workplace, Professor Chris Dobson and Dr Mary Dobson on Alzheimer's and other plagues, economist Professor Noreena Hertz on smart thinking and Professor Robert Mair on tunnelling into the future of our cities.

Professor Richard Evans, president of Wolfson College, will talk about the history of conspiracy theories, Dr John Swenson-Wright from the Faculty of Asian and Middle Eastern Studies will ask if North Korea is the perennial crisis state and Dr Robin Hesketh from the Department of Biochemistry will attempt to demystify cancer.

Several of the talks will take the form of a conversation: Professor Simon Blackburn will debate the uses and abuses of self love with journalist Rosie Boycott; novelist and playwright Biyi Bandele, a former Judith E. Wilson Fellow at Churchill College, will be in conversation with Dr Malachi McIntosh from the Department of English about migrant writing; Professor Henrietta Moore, William Wyse Chair of Social Anthropology, will talk about the future of civil activism with Ricken Patel, founding President of Avaaz, the world's largest online activist community; and psychologist Dr Terri Apter will debate how women follow, resist and play with the stereotypes that define them with author and alumna Zoe Strimpel.

Other Cambridge academics speaking at Hay are Professor Stefan Collini discussing higher education’s two cultures - the humanities and science - and historian Professor David Reynolds.

Peter Florence, director of the Hay Festival, said: "Cambridge ̽��ֱ�� nurtures and challenges the world's greatest minds, and offers the deepest understanding of the most intractable problems and the most thrilling opportunities. And for one week a year they bring that thinking to a field in Wales and share it with everyone. That's a wonderful gift."

Nicola Buckley, head of public engagement at the ̽��ֱ�� of Cambridge, said: “ ̽��ֱ��Cambridge series is a wonderful way to share fascinating research from the ̽��ֱ�� with the public. ̽��ֱ��Hay Festival draws an international cross-section of people, from policy makers to prospective university students. We have found that Hay audiences are highly interested in the diversity of Cambridge speakers, and ask some great questions. We look forward to another fantastic series of speakers, with talks and debates covering so many areas of research and key ideas emerging from Cambridge, relevant to key issues faced globally today."

For tickets, go to: www.hayfestival.org

A host of Cambridge academics, including Nobel Laureate Sir John Gurdon, will be speaking on subjects ranging from stem cell technology and Alzheimer’s to the future of North Korea and the history of conspiracy theories at this year’s Hay Festival.

Cambridge ̽��ֱ�� nurtures and challenges the world's greatest minds, and offers the deepest understanding of the most intractable problems and the most thrilling opportunities

Peter Florence, Director of Hay Festival

Hay Festival

Night shot at Hay Festival

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Genetic roulette in a new world

gm349 — Fri, 17 Aug 2012 17:00:56 +0000

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 “ ̽��ֱ��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.

̽��ֱ��feat was deservedly greeted with a fanfare of public interest unprecedented for any scientific project short of the early space missions. President Bush 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 ̽��ֱ��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.”

However, even more remarkable is what happened next. ̽��ֱ��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’. ̽��ֱ��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. ̽��ֱ��work was carried out by ̽��ֱ��Genome Institute at Washington ̽��ֱ�� 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 ̽��ֱ��, 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 knockout 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.

Dr Robin Hesketh, Senior Lecturer in the Department of Biochemistry and author of Betrayed by Nature, explains how advances in inexpensive, rapid gene sequencing and expression analysis is revolutionising cancer research and the development of new treatments.

MJ/TR (´???) from Flickr

DNA

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Everything we think we know – and know we don’t know – about cancer

amb206 — Wed, 06 Jun 2012 08:08:42 +0000

For 20 years or so Dr Robin Hesketh, Senior Lecturer in the Department of Biochemistry at Cambridge ̽��ֱ��, thought about writing a book. What he had in mind was one “that explained in the most simple way everything we think we know about cancer”. But he put it off, concentrating instead on experiments aimed at finding ways of stopping tumours growing and teaching Cambridge students about cells and how they signal to themselves and to each other. Then, one wet Sunday in 2008, he sat down at home and wrote the first words of Betrayed by Nature: ̽��ֱ��War on Cancer (Palgrave Macmillan, 2012).

Everything we think we know about cancer turns out to be quite a lot. We know that one in every three or four of us will get cancer during our lifetime – but that some of types can now be treated with very high success rates. We know that cancers are abnormal growths of cells – neoplasms – and that we’ve all got them in some form. Moles are unusual clumps of cells but are – almost always – unthreatening. We know that cancers can subvert our immune system, not only leaving us vulnerable to infection, but turning it from protector to traitor, giving succour to the neoplasm that can kill us. And we know that the lethality of these growths comes mainly from their acquiring the means to move home and, in wandering around the body, find a new locale in which to settle (a process known as metastasis).

Betrayed by Nature starts with a stroll through the history of cancer. As early as 1,600 BC the Egyptians were aware of conditions for which there was no treatment. Around 400 BC Hippocrates came up with the word carcinoma to describe tumours with a high density of blood vessels. Some 600 years later Galen, another Greek, is credited as the first person to use the word cancer (Latin for crab).

It wasn’t until the 18^th century that physicians began to link cancers to occupation and lifestyle. In 1713 Bernardino Ramazzini noted that cervical cancer was rare in nuns yet they were prone to breast cancer. A few years later Percival Pott concluded that sweeps (many were boys who were sent up chimneys naked) developed cancer of the scrotum as a result of soot lodging in the folds of skin. And then in 1866 Paul Broca, having studied his wife’s family tree, became the first to suggest it might be possible to inherit breast cancer. Even before those observations, the 17^th century pioneer Robert Hooke - a polymath whose inventive mind embraced physics, astronomy and the first blood transfusions - had identified the cell as the basic unit of life, laying the foundations for the field of cell biology.

Hesketh’s historical saunter leads us to the modern era of molecular biology. Launched by the revelation of the double helical structure of DNA in 1953, this field has seen an explosion of knowledge as the basic machinery of life has been unveiled. At its heart is the instruction code enshrined in DNA, in humans a sequence of three thousand million bases, and ‘DNA makes RNA makes protein’ has become ‘the central dogma’. With this has come the demonstration that thousands of diseases arise from corruptions in the code that are manifested in abnormal proteins. A well-known example is cystic fibrosis, an ultimately fatal condition caused by a mutant form of just one protein made in the lung.

Cancers too are mutation-driven diseases but with two crucial differences. ̽��ֱ��first is that cancers are driven by not one but several mutations acting in concert. As tumours develop they accumulate thousands of random mutations from which groups of perhaps half a dozen provide the driving force. ̽��ֱ��second is that the effect of ‘driver’ mutations is to cause cells to reproduce themselves abnormally. Many cells in the body replicate rapidly while some scarcely replicate at all after initial development is complete, and others can be ‘turned on’ when required, for example to repair injured tissue. ̽��ֱ��problem caused by cancer mutations is that they make cells multiply (in cell biology, multiplication is division) either too rapidly or at a time when, or in a place where, they shouldn’t.

Hesketh paints a picture of the infinity of flexible shapes that proteins can form and then illustrates the four major types of mutation that can act as cancer drivers. From this, the story moves to the effect of such mutants on the way cells behave – how normal cells are seduced into ignoring signals they should respond to, how cancer cells avoid suicide signals so that they survive with their mutant accelerators and defective brakes, adjusting their metabolism and co-opting nearby normal cells to promote their extravagant lifestyle, ensuring that survival and expansion of the tumour dominates. And then finally and fatally, we discover what happens when cancer cells spread in the usually fatal diaspora.

Betrayed by Nature addresses the unspoken question ‘if cancer is essentially so simple, how come it’s killing seven million people a year and the 12 million new cases in 2008 is set to become 15 million by 2020, when 30 million people on the planet will have cancer of some sort?’. Part of the answer is that we persist in doing things we know will get tumours going: sunbathing without protection (especially fair-skinned people), smoking (despite trends in some countries, the figure of over five million a year that tobacco use kills now, that’s one every six seconds, will rise to over eight million a year by 2030), eating poor diets and getting fat. On top of this, there’s the fact that we’re all living longer – and the longer we stick around, the more likely we are to develop cancer. In the Bronze Age the average lifespan was 18 years. Now world-wide it’s 66 and in the UK over 80 – facts that have the curious effect of making the cancer mortality rate in India (average life expectancy 64) half that of the UK.

̽��ֱ��other – and more complicated – part of the answer lies in DNA and its extraordinary flexibility. ̽��ֱ��random game of chance is that life means that the odds are heavily against a fertilized egg making it into a human being. When it does so it will have encoded in its DNA millions of variants, not only making each of us different to one another (the basis of DNA ‘fingerprinting’) but also giving us an individual molecular canvas upon which the layering of subsequently acquired mutations will inevitably lead to cancer – if we live to be 140. ̽��ֱ��cancers that emerge are so highly individual that each is unique. Each tumour has a different genetic make-up, even though historically pathologists have classified them into distinct categories.

̽��ֱ��astonishing individuality and complexity of each tumour is being revealed in molecular detail by current DNA sequencing methods and the final instalment of this saga is all about what Hesketh now regrets describing as “the greatest revolution in the history of medicine” in the book. He comments: “I should have substituted ‘science’ for ‘medicine’ because the technical advances that have occurred since the human genome was first sequenced in 2003 have already changed how we think about cancer and how we treat it and in the end they will affect everyone on earth.” ̽��ֱ��chapter ‘Let’s Sequence Your DNA’ notes that when the project to sequence the human genome was launched at the end of the 1980s the cost estimate was $1 per base: the current figure is one millionth of that—10,000 bases for one cent. ̽��ֱ��first sequencing machines in the early 1980s managed 10 kilo bases (10,000 bases) a day; the present rate is heading towards 100 million kb per day. So the cost has gone down by a factor of one million and the speed has gone up by 10 million.

All of this means that individual tumours can now be sequenced before treatment strategies are drawn up. For a number of the major cancers, sequencing has shown that tens of thousands of mutations accumulate as the tumours evolve in a process that Hesketh likens to ‘dynamic Darwinism’ as changes in DNA that confer a growth advantage permit clones to expand and dominate. ̽��ֱ��complexity of these mutational patterns is bewildering and it is almost beyond belief that a cell can survive such ferocious assaults on its genetic integrity, yet alone that a clone may emerge with the power ultimately to overwhelm its host.

A new vista in medicine is opening up, one that for cancer has already identified the major driving mutations and thus provided focal points for the development of new drugs. In parallel with the sequencing revolution, major strides are being made in ways of visualising tumours so that they can be detected with greater sensitivity and also that the effects of drug therapy may be followed. In addition, the progressive identification of molecular ‘biomarkers’ present in circulating blood will permit tumour detection at much earlier stages than is currently possible. These efforts are driven by the fact that surgery remains the first line of defence. More than 90% of cancer deaths come from metastasis. If they can be treated before they spread, by surgery and radiotherapy, the success rates are very high.

Amazing though the developments of the last ten years are, as is always the case in science, they build on what has gone before and Betrayed by Nature highlights the tremendous strides made in the second half of the 20^th century. ̽��ֱ��pioneering work of Sidney Farber at Harvard in the 1940s produced remission of childhood leukemia. Since then other very effective treatments have evolved, as illustrated by the progressive rise in five year survival rates for breast cancer and prostate cancer to over 85% and almost 100%, respectively. One of the greatest triumphs has been the development of vaccines that are essentially 100% effective in preventing cervical carcinoma by blocking viral infection that is the cause of almost all these cancers.

̽��ֱ��optimism in Betrayed by Nature derives from the evidence that the era we are entering offers not only the possibility of making an impact on cancers that have remained intractable but that, as detection is refined and the stock of specific drugs expands, we may even contemplate the replacement of surgery by highly effective chemotherapy. But Hesketh also has some simple messages that speak directly to today’s readers. “You can avoid a lot of things in life if you really want to: football, hamburgers, sex … but you can’t avoid cancer at least coming very close to you.” As for what we can do to maximise our chances of staying well, he says: “Don’t smoke – but if you do, give up – it’s not too late!” “Eat sensibly and do a bit of exercise” And he adds: “Men especially, if you think something’s wrong, follow JBS Haldane’s advice: don’t be macho – go and see your doctor.”

Betrayed by Nature: ̽��ֱ��War on Cancer by Robin Hesketh is published by Palgrave Macmillan, 2012.

A book written for the general reader, Betrayed by Nature: ̽��ֱ��War on Cancer by Dr Robin Hesketh, sets out in plain English what goes wrong in our bodies when cells begin to replicate in an abnormal manner, and what science is doing to address the disease that kills seven million people every year.

A new vista in medicine is opening up, one that for cancer has already identified the major driving mutations and thus provided focal points for the development of new drugs.

Robin Hesketh

Dr Robin Hesketh with flourescent images of (normal) human cell lines grown in culture

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