Developing the drugs of the future The MRCT Centre for Therapeutic Discovery

Developing the drugs of the future

The MRCT Centre for Therapeutic Discovery page 2 Profile: The Gray Institute for Radiation, Oncology and Biology, Oxford

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Developing the

drugs of the future

MARCH/APRIL 2009

CONTENTS

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Institute for Radiation, Oncology and Biology, Oxford

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18

Theannouncement

that a UK Centre for TherapeuticDiscovery

has been created, led by MRCTechnology,isvery

welcome news in this time

of economic turmoil. I was heartened to hear the Prime Minister’s recent comments that the economy needs to shift from its dependence on financial services towards science and technology. Investment in the UK’s scientific excellence is crucial now, perhaps more than ever before, because it is the key to economic recovery.

Moving forward, a broad discussion is needed involving research funders, the Government and the public, about the areas in which we’re likely to be most successful. Research funding is a balancing act between investment in ‘blue skies’ research and applied research for which the outcome is more visible from the outset. Both are absolutely essential because if we don’t support new ideas in all disciplines, very soon nothing is left to translate downstream. And we need excellence in a whole range of disciplines in order to make real advances.

For example, on page 18, you can read about a successful interdisciplinary collaboration which has offered unexpected new insights into cancer.

Representatives from the research community met late last year to agree a set of health research opportunities for the UK that target the biggest and most important health challenges we are likely to face over the next decade. This spring we are consulting academic and clinical stakeholders about these research opportunities before they are considered by the OSCHR Board. You can read about the outputs of this meeting on our website ( www.mrc.ac.uk/healthresearch) and contribute to this important discussion by sending us your comments and views – I look forward to hearing them.

Sir Leszek Borysiewicz

A new centre that will speed the discovery and development of drugs in the UK has been established in London, jointly funded by the MRC and MRC Technology.

The MRCT Centre for Therapeutic Discovery launched in April, will take advantage of the UK’s high quality academic research to discover and develop drugs for areas of unmet need. Using state-of-the-art computational and medicinal chemistry it will produce drug-like molecules with potential to become treatments. New antibody therapies will also be developed by the centre, taking advantage of MRC Technology’s expertise in ‘humanising’ antibodies - the process of genetically modifying rodent antibodies to make them more like human ones.

MRC Technology’s CEO, Dr David Tapolczay, explained: “For the first time, UK academics will have a dedicated centre with which to collaborate and progress their science to deliver tangible clinical benefit. In so doing, this initiative will help the UK to retain its world-leading reputation for innovation in drug discovery.”

The aim of the centre is to build on the capabilities and research capacity of the MRCT Drug Discovery Group. This will provide the UK with a national drug discovery resource which has the critical mass to be globally competitive. It will establish partnerships with academic scientists and industry to take the research towards clinical benefit.

Sir Leszek Borysiewicz added: “This centre of national excellence, in forming partnerships with academia, will provide a focus of knowledge and expertise. The initiative will benefit patients in the UK and around the world. It will also support innovation and provide a training ground for the next generation of scientists across Britain. It is these types of projects which represent the seed corn of the future UK economy by enhancing the UK’s leadership position in the scientific and technical disciplines of early stage medicine discovery.”

Dr Justin Bryans, Director of Drug Discovery at MRC Technology, explained that the centre will provide “a forum for education and training in the field of medicines research”, creating skilled jobs in medicinal chemistry and bioscience.

“Partnering our products with pharmaceutical and biotechnology companies worldwide will increase the value of the basic research that we support,” he added.

The centre has an annual operating budget of £6 million, secured from a range of sources including MRC translational funding. It will commercialise its products, but profits will be re-invested.

Update from

the MRC Chief

Executive

Bridging the academic-commercial divide The MRC is putting renewed effort into forging links between academia and industry this year, with a £3.2 million investment to create 45 new Industrial CASE studentships.

The studentships support multi-disciplinary research training projects between industry and academia.

Students are based at the participating academic institution, but spend a minimum of six months at a company, learning about how commercial research works and also gaining business-related training in, for example, project management or business strategy.

The studentships focus on building up the research workforce in new or growing areas of science, giving students a taste of the advanced skills and technologies in industry, and giving them a feel for industry’s competitive environment. Companies also benefit from the scheme, gaining from the MRC’s research excellence, and getting new ideas and insights.

Companies involved in the scheme in last year’s intake included Pfizer, Wyeth, GlaxoSmithKline, UCB Celltech and AstraZeneca.

AstraZeneca’s Jackie Wilbraham, who is a member of the assessment panel for CASE, is enthusiastic about the scheme: “These studentships give students a valuable opportunity to undertake part of their research in the world class research

facilities offered by companies. Students also gain an awareness of the drug discovery and development process and an insight into the some of the scientific challenges that pharmaceutical companies face.”

Peter Dukes, the MRC’s Head of Research Awards, added: “CASE students act as a bridge, opening up the perspectives of their MRC supervisors and colleagues to the priorities that drive research in industry and increasing opportunities for the translation of research.”

This year’s CASE intake begins in October 2009 and will focus on in vivo research. More information on the scheme is at:

www.mrc.ac.uk/Fundingopportunities/Studentships/

IndustrialCASE/MRC004608

Opening a window

on MRC research ^{INDUSTRY UPDATE}

Forthefirsttimeever,researchersand

the public can get a clear picture of the research that the MRC funds through a new interactive online web resource.

The MRC Research Portfolio (www.mrc.ac.uk/

researchportfolio) allows anyone to view research currently being funded by the MRC, as well as any research projects that have been completed since 1 April 2008. Visitors to the website can find out exactly what research is underway, who is doing it, and roughly how much money is being spent on it.

One of the aims of the MRC Research Portfolio is to increase the MRC’s accountability and transparency in its use of public funds.

John Jeans, MRC Chief Operating Officer and Deputy Chief Executive, said: “This is a really exciting development for the MRC. We are keen to throw open the doors on our research and show the public exactly what research their money is funding.

The portfolio also gives the UK research community an insight into our research so that they can position themselves according to the work that others are doing.”

The portfolio contains information on programmes and projects across the whole spectrum of MRC research – from research programmes in institutes, units and centres, to individual project grants and fellowships. Users can browse the portfolio by grant type, status, principal investigator and research organisation, or search the system using key words.

Search results can also be filtered, so that users can select the most relevant information.

Each research project shows a financial value, but it is important to stress that these figures cannot be compared across different project types.

Tony Peatfield, MRC Senior Responsible Officer for the portfolio, explained: “It’s important to note that for grants or fellowships the sum shown is the whole-life-value, but for a unit/institute programme or partnership/contribution the figure denotes annual spend. There are also important differences in the funding structures, so these figures can include different components. The financial information shown online is intended as an overview. If users have a specific question about the financial value of what is being funded in a particular area of science they should contact the MRC at corporate@headoffice.

mrc.ac.uk to discuss their requirements.”

The MRC Research Portfolio can be found at:

www.mrc.ac.uk/researchportfolio

7

Securing skills today for tomorrow’s scientists

Whole-animal physiology and pharmacology research in the UK is being boosted with a

£12.3 million joint funding initiative to halt the loss of specialist skills and help forge closer links with industry.

Translation of basic research discoveries into new treatments depends on testing their safety and efficacy in integrated biological systems, including whole animals.

But recently the number of scientists who have the specialist skills to perform these studies has been declining as established researchers retire, and fewer universities offer whole animal science at undergraduate and postgraduate level.

A capacity-building programme in integrated mammalian biology has been set up to meet this challenge. The programme aims to equip researchers from undergraduate to postdoctoral level with expertise and skills, such as best practice for using animals in research and high quality experimental design. It is jointly funded by the BBSRC, the British Pharmacological Society (through their Integrative Pharmacology fund, supported by AstraZeneca, GlaxoSmithKline and Pfizer), the Department for Innovation, Universities and Skills, the Higher Education Funding Council for England, the Scottish Funding Council and the MRC.

Links with industry

Launched in 2005 and now in full swing, the programme has established four university-based integrative

mammalian biology centres which are acting as ‘honey-pots’

for public-private funding opportunities. Two of the ‘virtual centres’ are based in London at Imperial College and King’s College, and the other two are joint consortia between the universities of Manchester and Liverpool, and the universities of Glasgow and Strathclyde.

“The capacity building awards are proving to be an excellent example of how public and private funding organisations can work together to rebuild an essential area of UK biomedical research,” explains Dr Mike Collis, chairman of the British Pharmacological Society Integrative Pharmacology Fund, and coordinator of the project.

For example, the universities of Liverpool and Manchester are hosting the MRC Centre for Drug Safety Science. This centre brings together human genetics and in vivo science with industrial partners to improve drug design and the screening processes used to minimise the risk of adverse drug reactions.

Creating closer links with industry also encourages industrial scientists to get involved in university-based teaching. Recently AstraZeneca held an experimental design day at King’s College London, while a similar course held in Manchester will be extended to an annual event though industrial sponsorship.

Teaminguponeducation

With their own educational projects and activities now fully established, centres are also starting to work together.

Imperial College and King’s College London are planning to develop a joint state-of-the-art teaching and research facility for telemetry, an in vivo technology which can be used to monitor animals remotely. The technology allows for fewer animals to be used for research and minimises disruption to their normal behaviour.

The capacity-building awards are also fostering

collaborations between whole animal scientists within the

partner institutions. New-blood lecturers and academic fellows have been recruited. These include a Pfizer- sponsored Chair in Integrative Biomedicine and ‘3Rs’

lecturer at King’s College, enhancing the profile of in vivo physiology and pharmacology as essential disciplines.

Mike Collis adds: “We are pleased to report that the potential number of PhD studentships held at the centres has already doubled from the original 50 directly funded through the integrated mammalian biology capacity- building awards, and we expect the number to increase further over the next three years.”

In addition, the MRC recently awarded funding to seven universities for 22 PhD studentships focused on in vivo animal sciences training, some of which were also part- funded by the British Pharmacological Society. And the MRC and BBSRC have also funded 12 capacity-building Masters studentships in five universities for in vivo sciences.

Engaging the wider community

Informing the wider research community and the public about the importance of animal-based research is another important activity for the centres. Recently, a public discussion on the use of animals in medical research was organised by staff at the University of Glasgow as part of its Café Scientifique. Meanwhile, both Imperial College and the University of Manchester have outreach programmes aimed at school children and Members of Parliament, which include talks and a tour of their animal facilities.

The centres will outline their research and educational activities at a Scientific Meeting in autumn 2009, which will also include a careers session for students. For further information, contact Dr Mike Collis by emailing mc@bps.

ac.uk. More information and links to the four centres are available in the April 2009 BBSRC Business magazine at www.bbsrc.ac.uk/publications/business

A major UK clinical study in the adult- onsetformofdiabetespassedasignificant

milestone in February, recruiting its 6,000th volunteer.

The Norfolk Diabetes Case Control Study is a collaboration between the MRC Epidemiology Unit in Cambridge and the diabetes team at the Norfolk and Norwich University Hospital and University of East Anglia.

Dr Claudia Langenberg of the MRC Epidemiology Unit said: “The fantastic response of the people in Norfolk to our study has given us a unique opportunity to investigate how genes influence the development of Type 2 diabetes and its complications.”

The study has recently contributed to the discovery of a gene that is strongly linked to high blood sugar levels and an increased risk of Type 2 diabetes. The gene is involved in the way the body responds to the 24 hour day-night cycle. These findings, the result of a large international collaboration, were published in Nature Genetics in December 2008.

The study, jointly led by Professor Mike Sampson in Norwich and Professor Nick Wareham in Cambridge, began in 2003 and aims to recruit 10,000 people. It is jointly funded by the MRC and the Wellcome Trust.

The announcement coincided with news that UK Biobank, another major study part-funded by the MRC, has now reached its halfway mark by recruiting 250,000 people. UK Biobank relies on the altruism of the UK public to submit to being questioned, measured and analysed over 30 years in order to build up a major resource to tackle diseases like cancer and heart disease. It now expects to recruit its 500,000th person in mid-2010, ahead of schedule.

Diabetes study gains the help

of 6,000 volunteers

Kay Davies becomes a

Desert Island Discs castaway

Aled Jones, the Beatles and Schubert were amongProfessorDameKayDavies’music

choices when she joined the ranks of the distinguished and famous who have appeared onBBCRadio4’sDesertIslandDiscs.

Kay, whose many roles include being Director of the MRC Functional Genomics Unit, talked to presenter Kirsty Young on the 15 February broadcast about her life and work, and the music which has been important to her along the way.

The tracks she chose to take to the fictional desert island included The Skylark by Aled Jones, a reminder of childhood holidays in Wales. Another choice was a recording by a group of Kay’s former colleagues from the Institute of Molecular Medicine, The IMMposters. She recalled hearing them play at parties and said they represent “the passion of science, and the happiness of the whole place”.

Over the last 20 years Kay has been unravelling the genetic basis of Duchenne Muscular Dystrophy (DMD), a devastating muscle wasting disorder affecting boys which renders them wheelchair bound by the age of 12 and usually kills them by early adulthood. In the early 1980s she developed a simple diagnostic test for screening pregnant women who may be at risk. And clinical trials of a new treatment will begin later this year based on her group’s research into a protein called utrophin, which is similar to the one absent in DMD. Kay hopes the therapy might prevent the disease’s effects if boys are treated as soon as they are diagnosed with the disease. She told Kirsty she was “really optimistic” that within the next 10 years there would be an effective treatment.

Kay spoke about the most significant breakthrough of her career, which happened on a Sunday morning in 1989.

She was developing film to find out where a particular gene sequence was localised on the chromosome and discovered another gene that was very similar to the one that is missing in DMD boys – the one encoding utrophin.

“It wasn’t until that ‘eureka’ moment on a Sunday morning that we even dreamt that there might be another gene that might help with the treatment, so we got very, very excited about that,” she said.

Reflecting on the secrets of her success, Kay said that perseverance and patience are important for a research career – skills she displayed from an early age in primary school. “I loved solving problems” she said, “I was very tenacious and would sit in my room until I had finished the problem…I am a sticker.”

Although many hours spent problem-solving in the lab might leave some people detached from the outcome of their research, this is not the case for Kay. She regularly meets DMD sufferers and their families at conferences, and said that she admires their courage. “They start off playing football with their friends and progressively they can’t do that any more. And they’re very innovative in the way they fight the disease and make the best of life…I think everyone is touched by DMD boys.”

The book Kay chose to take to her desert island was Alan Bennett’s Untold Stories. And her luxury? “It’s very boring but it has to be a piano because I can be creative…and I can even make up my own tunes”.

Yacht racer’s urine holds nutritional secrets

YachtracerDeeCaffarinotonlymadehistory

inFebruarybybecomingthefirstwomanto

sail solo around the world in both directions, but also took part in MRC research during her latest epic race, by collecting her urine.

Dee spent three months at sea taking part in the Vendée Globe – a single-handed, non-stop, round-the-world sailing race – which she finished in sixth place. Researchers from the MRC Collaborative Centre for Human Nutrition Research in Cambridge and from Leeds Metropolitan University set out to determine Dee’s energy expenditure during the 28,000- mile race to gain more information on the energy needs and calorie intake required in such physically demanding conditions.

During the race, Dee drank doubly-labelled tracer water and collected and filtered her urine for five days, storing it for testing later on. Tracer water is slightly heavier than ordinary water, which allows scientists to differentiate between the two.

By measuring the amount of tracer water Dee excreted in her urine at different times, the researchers will be able to target her diet in future to match the different demands of each stage of the race. Dee took measurements at two different stages: the relatively calm Atlantic Ocean leg, and the tougher Southern Ocean part of the journey, during which severe wind and wave conditions really tested her physical strength.

MRC Human Nutrition Research’s Antony Wright, who is coordinating the study, said: “The opportunity to measure Dee’s energy expenditure with doubly-labelled water provides us with an improved understanding of the energy costs and dietary requirements of such specialist athletes, and that could directly be used to improve the future training regimes of all athletes across a whole spectrum of competitive sporting activities.”

Dee added: “Mother Nature can be completely unpredictable and definitely challenges you to your maximum, and you just can’t replicate a race like this in a laboratory.”

PROFILE

ThE GRAY InSTITUTE fOR

RADIATIOn, OnCOlOGY AnD BIOlOGY, OxfORD

Perhaps the best known health statistic you are ever likely to memorise is the one about cancer; that around one in three of us will get it at some point in our lives. You might look at your friends and family and wonder who it could be? You might already know.

Cancer is an indiscriminate killer and while mortality rates have decreased in the past 20 years, the incidence rate has increased.

The pressure on NHS resources to deliver a successful programme of care to each and every cancer patient is colossal, making financial investment in cancer research to find more efficient and effective methods of treatment a top health priority.

A collaborative venture

The Gray Institute for Radiation, Oncology and Biology, based in the new glass-enveloped Old Road Campus Research Building on the Churchill Hospital site in Oxford, is one such investment. Its foundations lie in a scientific initiative to create a world-class research centre for radiobiology that had the capabilities and resources to explore the translational possibilities of the field. This initiative was a collaborative venture; the Gray, named after the English physicist and radiologist, Louis Harold Gray, is owned and managed by the University of Oxford Medical Sciences Division with funding from both the MRC and Cancer Research UK.

The walk from bench to bedside is a short one for the Gray’s researchers. The institute is within a stone’s throw of the Churchill Hospital – a centre for cancer services and home to one of the busiest oncology departments in the UK. The Churchill also houses the new Oxford Cancer Centre, a £109 million project to consolidate cancer services across the city, uniting the main elements of cancer diagnosis, investigation and treatment on to

one hospital site. This juxtaposition makes perfect sense;

basic research can work hand-in-hand with the testing of new agents in real patients.

Directing the institute’s extensive programme of research is Professor Gillies McKenna. Gillies has gathered scientific expertise from across the world (his team also includes researchers from the former Gray Cancer Institute in Northwood and MRC Radiation and Genome Stability Unit at Harwell) to look at ways to improve cancer treatments using radiation.

He explains: “Tumours must have an Achilles’ heel, a weak point – we just have to find it. The focus of our work here at the Gray is on looking at how the effectiveness of cancer treatments such as radiotherapy can be improved.”

DNAdamagesignalling

Our cells are bombarded by damaging factors every day;

whether that damage is a result of smoking, sunbathing or genetic and environmental factors, it will affect our DNA. Cells in the human body have many pathways and mechanisms to repair DNA breaks and damage when they occur. If the damage is too great, the cells might self- destruct via a process called apoptosis, or their growth and division is halted so that the damage can’t spread.

A common feature of many cancers is that there are defects in one or more repair processes which enable them to dodge these growth controls. Cancer cells get a green light to keep reproducing. Without a stop signal, they will keep duplicating and eventually a tumour will form.

However, this genetic damage and the subsequent side- stepping from the body’s normal controls on growth may also make them very susceptible to treatments that

block DNA repair. It is this weakness that many scientists at the Gray are now exploiting. If they can block or inhibit the remaining repair systems, the body should be able to knock out the cancer cells while normal cells will remain undamaged.

This approach has multiple benefits; the cost and length of treatments could be vastly reduced; there would be less patient intervention; and by using drugs rather than standard cancer treatments such as chemotherapy (which is toxic to all dividing cells) the side-effects would be lessened.

Professor Thomas Helleday and his group study the genes BRCA1 and BRCA2 that predispose women to developing breast and ovarian cancer. Women with defective versions of the genes have up to an 80 per cent increased risk of developing these cancers. Thomas explains: “In breast and ovarian cancers, a pathway that repairs mistakes when DNA is replicated no longer works, and the cancer cells are reliant on a different process based on a protein called PARP for survival. We have shown that these specific cancers could be targeted using an existing drug that inhibits the PARP protein.”

This concept has now been licensed to AstraZeneca and phase II clinical trials of the drug involving a few hundred patients began in May 2007.

Advanced pancreatic cancer

The idea of using an existing drug to treat cancers is being adopted by increasing numbers of researchers.

Clinical scientist Dr Thomas Brunner is looking at the effect of a drug called Nelfinavir – an existing anti-retroviral compound – as a candidate for sensitising tumours to radiation. Thomas says:

“Creating new inhibitor compounds as viable clinical interventions can be a lengthy and expensive process.

An approach that circumvents this delay is to adopt drugs currently in clinical use for other diseases that have the desired effect.”

Thomas is assessing the viability of Nelfinavir as a treatment for advanced pancreatic cancer, a disease that has a very poor prognosis.

In Phase I clinical trials, Thomas and his team treated 10 advanced pancreatic cancer patients, all of whom had inoperable tumours, with the drug plus a subsequent course of chemoradiation. The results were startling. Thomas says: “Normally, following a course of chemoradiation treatment over many months, a pancreatic tumour can be shrunk but not destroyed.

Using this inhibitor, compound cancer cell growth was slowed and the cells became more sensitive to radiation treatment.”

Of the 10 patients, 60 per cent had tumours that were now resectable, and up to 90 per cent of their tumours had been destroyed. In one patient there was 100 per cent destruction. Two years later, more than half of the trial patients are still alive. Thomas is now awaiting approval to begin Phase II trials.

RESEARCH CENTRE NEWS

DunnrebornastheMRCMitochondrial

Biology Unit

The MRC Dunn Human Nutrition Unit in Cambridge is shifting its research focus to work solely on the biology of mitochondria, the “powerhouses” inside cells. To mark this change it has been renamed The MRC Mitochondrial Biology Unit.

The unit’s research includes investigation of how mitochondria convert energy in the food we eat into fuel to power the body, how the small DNA molecules in mitochondria are replicated, and how to avoid the effects of reactive oxygen species formed in mitochondria, which are implicated in ageing and cancer.

Over the last decade the MRC Dunn Human Nutrition Unit devoted much of its research to this field, while also looking at how diet can cause or prevent cancer.

The unit moved some of these diet and cancer activities across to the Centre for Nutritional Epidemiology in

Cancer Prevention and Survival (CNC) at the University of Cambridge in 2004. Following a strategic review of UK nutrition research last year, the MRC has decided to transfer the last of these activities to the CNC and to rename the Dunn to reflect its new specialism.

Unit Director Professor John Walker, who was instrumental in bringing about this new research focus, told Network: “This strategic change acknowledges the growing realisation that mitochondrial dysfunction is linked with major neurodegenerative and metabolic diseases such as Parkinson’s and Alzheimer’s, diabetes and obesity, and possibly to the ageing process itself. As part of this realignment, the unit will develop its growing interests in the cell biology and genetics of mitochondria and will continue to strengthen its links to basic and translational clinical science.”

Professor Walker will lead on the shift in emphasis until he steps down from being Director in 2011.

applied to many kinds of cancer. Thomas Helleday says:

“In the future, you could imagine screening a patient’s cancer for defects, picking out the precise inhibitors to target the remaining DNA repair pathways, and treating that person’s tumour in a very targeted way.”

Tumourmicroenvironment–imaging Analogies to Dr Who monsters would not be remiss when talking about the nature and behaviour of cancer tumours. A rapidly growing tumour cannot feed itself sufficiently and will become starved of oxygen, or hypoxic. In the hunt for more oxygen and energy, it can become aggressive and invasive; creating its own blood supply and monopolising existing blood vessels. A hypoxic tumour will disperse cancer cells throughout the body (metastases) and is resistant to chemotherapy and radiotherapy.

Several research groups are investigating how the tumour microenvironment can be improved so that it becomes more susceptible to treatment, so reducing the chance of metastasis. Gillies says: “This area of research is one of our greatest strengths and we’re supported by fantastic imaging and radiation physics facilities, plus a team of experts from across the university; chemists, engineers, mathematicians and medics as well as biologists.”

Dr Martin Christlieb is one such expert. A chemist by training, Martin is working on new methods of assessing tumour oxygenation that can hopefully help medics to deliver appropriate treatment regimes to patients. Martin says: “Two promising imaging techniques are PET (positron emission tomography) and SPECT (single photon emission computed tomography). These techniques rely on delivery of a radioactive isotope selectively to the hypoxic tissues so that the presence and extent of hypoxia can be visualised and measured.”

The patient is injected with a radioactive isotope that is carried to the tumour site. Hypoxic cells trap the isotope, which emits radioactivity that is then picked up by the scanner. A clinician can then establish the location and spread of hypoxic areas within the tumour.

Large areas of hypoxia can be bad news and may require different management. So what is it like to be a chemist in a biologist’s world? Martin says: “Moving from one discipline to another is a very steep learning curve – like doing a second degree and second PhD at the same time. On the plus side, once you’ve learned to speak the

can act as a bridge between the biological and physical sciences.”

Tumourmicroenvironment–metastasis Non-malignant cells such as inflammatory cells, fibroblasts, smooth muscle cells, and endothelial cells interact with tumour cells and can influence how the disease spreads.

Professor Ruth Muschel’s lab has been using imaging techniques to examine the mechanisms that underlie the development of metastases in different organs such as the lung, liver and brain. She says: “These methods allow us to see tumour cells as they interact with blood vessels in their target organs. For example, we can visualise clots forming around tumour cells and show that inhibition of these clots can inhibit metastasis. We can also observe the tumour cells exiting from the blood vessels. By observing these processes we are gaining a better understanding of how metastatic cells interact with the host. This in turn helps us to evaluate targets for therapy and for metastasis detection.”

Radiopharmaceuticals

An alternative approach to using radiotherapy to kill cancer cells is to inject radioactive chemicals into the bloodstream. This method involves using radioisotopes which precisely target the cancer cells; killing them but leaving healthy cells alone.

Dr Kate Vallis, who leads the Gray’s Experimental Radiation Therapeutics Group, explains: “The drugs we are developing consist of a radioisotope linked to a protein which is capable of homing in on molecules that are particularly abundant in cancer cells,” she says. ‘We design the drugs in such a way that they can get into the nucleus of the cancer cell and deliver radioactivity directly to the DNA which is then damaged, so that the cancer cell dies. We use radioisotopes that emit a type of radiation that can only travel a very short distance, less than the diameter of a cell. If you can get these drugs into the nucleus they can deliver radiation at that site only and normal surrounding cells will be unaffected.”

So far, one of the radiopharmaceuticals that Kate’s team has been developing has been tested for safety in breast cancer patients. Later this year, it will be tested in a second trial, this time including patients with cancers of the head, neck, lung and breast.

There is so much ahead for the Gray Institute, and Gillies has high hopes for its future research: “Imaging is a key driver behind improvements in the field of radiation oncology. We want to develop our imaging methods so that clinicians can understand what’s going on in a tumour without having to touch the patient;

in turn this will speed up the processes of diagnoses, prognoses and treatment.”

Supporting such research aims does not come cheap but the institute is at the heart of some significant financial investments. Funding is in place for the development of a specialised cancer imaging centre as part of a £50m

uses for existing cancer imaging technologies. The MRC contributed £3m to the project.

Secondly, the University of Oxford is to build a new cyclotron – a particle accelerator – to produce radioactive tracers for cancer studies. This project, to which the MRC contributed £2m, will also support work at the Gray.

As long as there is cancer, there will be research. And with the life-saving advances being made in research centres such as the Gray, perhaps that statistic about ‘one in three’ is about to change?

GenderdivideinScotland’salcohol-relateddeaths

Twice as many men die every year in Scotland from alcohol misuse than women, research by the MRC Social and Public Health Sciences Unit and the University of Glasgow has revealed. The researchers consolidated existing data showing that alcohol-related fatalities in both genders have doubled over the past 10 years, and also found that death rates within Scotland vary considerably. The findings show that the men’s death rate from alcohol is 38 per 100,000, while the women’s rate is 16 per 100,000.

On average, the study found that 999 Scottish men and 448 women die each year from the health consequences of alcohol misuse. The Greater Glasgow area had the highest occurrence of alcohol-related deaths, though the authors identified areas with high rates in all regions of the country.

Dr Carol Emslie of the MRC Social and Public Health Sciences Unit, said:

“Although the study shows remarkable differences from place to place in alcohol-related deaths, the areas in which alcohol-related deaths are a particular problem for men are largely the same for women. The results suggest to us that both men and women are vulnerable to the social, economic and cultural pressures which can make people drink too much.”

Published online at www.biomedcentral.com

Brain feels gain from rival’s pain

Seeing someone we envy suffer misfortune causes increased activity in the part of the brain that processes feelings of reward, research part-funded by the MRC suggests. The research team used functional magnetic resonance imaging (fMRI) to measure blood flow to different parts of the brain in a group of student volunteers. Corresponding images showed which parts of the brain were busiest when responding to different scenarios. When the most envied student suffered a misfortune, greatest activity was observed in the greater ventral striatum, a brain region which perceives reward. The results also showed that the part of the brain that deals with thoughts of pain, the dorsal anterior cingulate cortex (dACC), also processes envy. Activity in the dACC was shown to be greatest the more superior an envied person was perceived to be. The study was led by Dr Hidehiko Takahashi of Tokyo Medical and Dental University in Japan. The paper’s co-author, Dr Dean Mobbs of the MRC Cognition and Brain Sciences Unit in Cambridge said: ‘‘These findings frame a theory that envy is a condition in which a person experiences cognitive aspects of pain, and that this pain is relieved when something unfortunate happens to an envied person: that is, ‘schadenfreude’ occurs.”

Science, 13 February 2009; 323: 5916; 937–939

15

RESEARCh ROUNDUP

Bad behaviour at school creates lifelong problems Information gathered over 40 years has shown that young people who misbehave at school are more likely to experience difficulties in their adult lives. Professor Ian Colman and colleagues studied data provided by the MRC Unit for Lifelong Health and Ageing from the MRC National Survey of Health and Development (the 1946 Birth Cohort). They looked at the health and social problems of over 3,500 people whose behaviour was rated by their teachers when they were 13 and 15 years old. Later, when the participants were aged between 36 and 53, they were asked about their mental health and social and economic status. The study found that those who had severe or mild conduct problems in adolescence were more likely to leave school with no qualifications and go on to experience depression, anxiety, divorce, financial difficulty and other problems in adulthood. This result held true even taking into account other factors such as gender, father’s social class, adolescent depression and anxiety and cognitive ability. Professor Colman said: “Given the long-term costs to society, and the distressing impact on the adolescents themselves, our results might have considerable implications for public health policy.”

Published in the British Medical Journal online, January 2009

Sticky antibodies block prion disease

Antibodies that stick to a brain prion protein called PrP could help prevent prion infection diseases like variant CJD, research suggests. In infectious prion disease, prions convert naturally-occurring PrP into a corrupted form called PrPSc that has a different shape. PrPSc then builds up in the brain, causing the death of brain cells and other symptoms of prion disease. Molecular biologists from the MRC Prion Unit at University College London and biophysicists at the University of Liverpool used X-ray crystallography to visualise how the antibodies and prion protein stuck together at a molecular level. They identified a monoclonal antibody which binds very well to PrP and then tested it in cells and in the brains of mice. By sticking to PrP, the antibody prevented the prions from converting protein into PrPSc and stopped the prion infection in its tracks.

Professor Samar Hasnain, Max Perutz Professor of Molecular Biophysics at the University of Liverpool, said: ‘‘These results are a great example of research crossing disciplines to share the skills of molecular biologists and biophysicists to solve problems associated with human disease.’’

Proceedings of the National Academy of Sciences: Advanced online publication

Professor Mark Marsh has been appointed as the new Director of the MRC Laboratory for Molecular Cell Biology (LMCB) and Cell Biology Unit at University College London. Having served initially as Acting Director of the unit since March 2006, Mark has now been appointed on a permanent basis. Mark’s research group at the unit has focused on the mechanisms of HIV assembly and how this might be used to understand and combat HIV infection. He said “I’m very pleased to have been offered this opportunity – the LMCB is a great research institute and I think together we can make it still better.”

The National Osteoporosis Society’s inaugural Duchess of Cornwall Award has been awarded to Professor Cyrus Cooper, Director of the MRC Epidemiology Resource Centre at Southampton University, for his outstanding contribution to the field of osteoporosis. Professor Cooper leads internationally competitive research into the causes of musculoskeletal disorders, including osteoporosis. He said: “To be recognised with this award is an incredible honour, and I only hope that my work in the field has made a practical difference to people whose lives are affected by osteoporosis.”

Sir Leszek Borysiewicz added his congratulations: “I’m delighted to hear this news. The award is a great achievement for Cyrus and the unit, underlining the important contribution to osteoporosis that they have all made.”

Professor Sir Philip Cohen, Director of the MRC Protein Phosphorylation Unit in Dundee, has been recognised for his Leading Contribution to Life Sciences in Scotland. Sir Philip received a Scottish Enterprise Life Sciences Award in February at the agency’s 2009 Annual Dinner. Sir Philip recently set up the Scottish Institute for Cell Signalling at the University of Dundee, which he also directs. He is the founder and co-director of the university’s Division of Signal Transduction Therapy which received a Queen’s Anniversary Prize for Higher and Further Education in 2006. Sir Philip said: “I am delighted and honoured to receive this Life Sciences award for my contributions to this field. This award also recognises the extremely high standards and quality of work that is carried out at the MRC Protein Phosphorylation Unit at the University of Dundee.”

MRC Professor at Liverpool University Ole Petersen has been honoured with the publication of a ‘Festschrift’ – a tribute to his work – by the major international journal Acta Physiologica. The January 2009 issue of the journal contains a collection of review articles and original articles based on lectures given at a symposium held to mark Professor Petersen’s 65th birthday, at the Royal Danish Academy of Sciences and Letters in Copenhagen. Professor Petersen was the first to identify and characterise calcium-activated ion channels in epithelial cells. He was elected a Fellow of The Royal Society in 2000 and was awarded a CBE for Services to Science in 2008.

MRC PEOPlE

Top Professor Mark Marsh.

Middle The Duchess of Cornwall presenting Professor Cyrus Cooper with his award.

Bottom Professor Sir Phillip Cohen (centre) being presented with his award by John Swinney, Finance Minister in the Scottish Government and Rhona Allison, Senior Director Life Sciences, Scottish Enterprise.

nurturing the stem cell therapies of tomorrow

TheMRCinvested£3millioninseven

new awards to support early-stage stem cellresearchinJanuary.Thefundingwill

bolster the most promising preclinical stem cell research so that it can be advanced more quickly into human trials.

A team at the University of Oxford led by Dr Paul Fairchild will look at how to avoid immune system rejection of transplanted stem cells, which is a serious barrier to the use of stem cells in regenerative medicine.

Using animal models, the team will investigate whether the immune system can be persuaded to tolerate the presence of transplanted stem cells. It will also look at the risks of inadvertently transplanting rogue cells which could develop into tumours – and whether or not these cells can be sought out and destroyed by the host’s immune system.

Professor Charles ffrench-Constant and his team at the University of Edinburgh will develop an animal model for diseases which affect the insulating sheath around nerves, such as multiple sclerosis. Meanwhile at the University of Birmingham, Dr Philip Newsome will lead research into transplanting human embryonic stem-cell-derived liver cells – which might one day lead to ways of regenerating damaged liver tissue.

Other awards will pave the way for future stem cell transplantation therapy by tracking what happens to stem cells which have been transplanted into animals. A University of Liverpool-based team will use nanoparticles to follow transplanted neural stem cells as they differentiate to form different parts of the nervous system, while at the Institute of Psychiatry in London, scientists will transplant cells into animal models of Huntington’s disease and then follow their progress using cellular imaging techniques such as fluorescence.

19

What do you get if you put together a theoretical physicist and a biologist? As it turns out, a new way of accurately predicting how tissues behave which could lead to new cancer treatments. Network visited the MRC Cancer Cell Unit at the Hutchison/

MRC Research Centre in Cambridge to meet an unlikely pairing of scientists which has produced fruitful results.

Six years ago Dr Phil Jones, an oncologist at the MRC Cancer Cell Unit, was working on the genetic labelling of individual stem cells in mouse skin in the laboratory, tracking the fate of cells as they divided. After several years he had generated a huge amount of data, but he was stuck on how to interpret it. A colleague of Phil’s happened to mention his problem to her husband, Professor Ben Simons, a theoretical condensed matter physicist with a penchant for statistical analysis. Through this serendipitous link, physicist and oncologist began to work together with the support of an MRC discipline- hopping grant.

Combining their very different skills and backgrounds, Ben and Phil have devised a way of predicting the fate of cells and tissues over a long period, which could cut a year’s research down into a couple of weeks, significantly reduce the amount of animals needed for research, and offer new insights into how cancer cells behave.

Until Ben and Phil came together there had been a long-standing theory that mouse skin was maintained by a slowly cycling population of stem cells. These stem cells then divide, so the theory went, to produce a transitional cell population which divides a few times before division stops permanently. However, when Ben helped Phil to analyse his data, they found out that this wasn’t the case.

Ben tackled the data with mathematical concepts first raised by Charles Darwin’s cousin, Sir Francis Galton, who has a shady reputation as the father of eugenics. Galton considered the probability of having a male heir – an important matter for the Victorian upper classes who wanted to prevent family names from becoming extinct.

A century on, the mathematics that underpinned these ideas turned out to be just the job for analysing the lineage of skin cells.

Ben explains: “We discovered that all the cells are equivalent and when they divide they essentially throw the dice, realising a balance between dividing to produce clones of themselves and differentiation into other cell types. The data showed that with equal probability they may go down a route where they symmetrically self- renew or a route where they terminally differentiate.”

Phil adds: “By looking at the fate of hundreds or thousands of cells we were able to write an equation for how the tissue keeps itself going, how it maintains itself.

The equation allows us to predict how cells will behave over a long period – for example a year or six months, with great precision.”

By going back to old, previously published data, Ben discovered that they had stumbled across a ‘common organisational principle’ which describes how tissue maintains itself in many different organisms and tissue types. So far, he has shown that similar principles holds true not just in mouse skin but also in sperm cells and in the cells lining the intestine.

The findings could significantly reduce the number of animals needed for research. The skin of each animal contains thousands of clusters of labelled cells, the size of which give accurate information on how cells

hopping across disciplines solves research puzzle

have behaved since the start of the experiment. By doing a short-term experiment in just a few animals, a mathematical equation can be developed which will predict the results of a long-term experiment.

Phil says: “The system could also be used in genes which are linked with cancer, to study quantitatively how the disease would evolve. Since we know what normal is from the equation we can see what a cancer gene does that is abnormal. Therefore we’re not just getting data quicker, but we’re getting data that you could not get any other way.”

Phil and his team are now conducting research into cancer tissue cultures, and hope to be able to use the new findings even more widely. “We believe this ability to predict is the threshold of a new field in biology which could help us to understand processes like ageing, cancer, gene function or drug activity in tissues in a quantitative way,” he says.

But what were the challenges of approaching the research from two completely different disciplines? Ben says: “The main problem is the language barrier – that requires enormous amounts of patience, flexibility and cooperation on both sides. So I’ve been really lucky that Phil has indeed been very patient and careful in the way that he has explained things.”

On the whole, the pair are very positive about their experiences of interdisciplinary collaboration. Ben says: “There were important conceptual insights imported from physics which have really stretched our understanding, and informed it.” For example, the data that Ben trawled through had been published in the past, but the hidden correlations in it had gone unnoticed until Ben looked at them.

“On the flip side of that, theoretical physicists can’t produce their own data, they can only theorise – and we can be fickle and cross into any discipline, it doesn’t matter what the data are. I think that biology offers immensely fascinating and brand new problems for a theoretical physicist to get involved in,” says Ben.

The MRC discipline-hopping grant that supported the work was crucial to the collaboration’s success, allowing Ben to simultaneously run another research programme in theoretical ultra-cold atom physics at Cambridge University’s Cavendish Laboratory. Ben says: “Most of the work that’s been done in the last 18 months would not have been possible without the effective sabbatical that was provided through the discipline-hopping grant. It enabled me to spend all of my time working down here at Addenbrooke’s Hospital, mixing with biologists, getting to know much more about these different problems and gave me the opportunity to go outside Cambridge and forge absolutely new collaborations – so I’m enormously grateful to the MRC for providing this very valuable grant.”

Read more about Ben and Phil’s research at

www.hutchison-mrc.cam.ac.uk/Research/

Phil_Jones/index.html

PUBlIC

ENGAGEMENT

Theimportanceofsciencetopeople’s

everyday lives and the UK economy is the subject of a new government campaign aimed at the general public and supported by the UK Research Councils.

Science: [So what? So everything] was launched by the Prime Minister at an event at Downing Street in January.

High profile guests including author Terry Pratchett, businessman James Caan and scientist and presenter Kathy Sykes took part in a discussion about how science can be taken to a wider audience to encourage more public involvement and understanding.

Terry Pratchett said: “Science and its products are in practically everything we touch, see and do. I use it every day! From my computer, to the medication I take and the telescope I use – whenever the clouds allow. We have turned ourselves into creatures of science. It is up to us to learn how to use science wisely because I don’t think we’ll find such another wonderful resource.”

Science Minister, Lord Drayson, added: “Britain is a world- leader in science, second only to the United States, with many of the most important scientific discoveries and inventions having been made here. Continued success in science is vital to our future – and yet there is still the perception among many of our people that science is too clever for them or elitist in some way. We must challenge myths like these if we are to build a prosperous, science-literate society, able to tackle the difficult issues that modern science presents and work them through to create the jobs and growth of the future.”

More information about the campaign can be found at:

www.direct.gov.uk/sciencesowhat

Bringing home the relevance of research

EVENTS DIARY

Dragon’sdenforinnovativescience

MRC scientists will get the chance to pitch ideas for translational research projects to a panel of commercial experts on 11 May at an Innovation Afternoon being held by MRC Technology. The winner will receive £5,000 towards the research of their lab. The event will take place from 2-5pm at the Laboratory of Molecular Biology’s Max Perutz Lecture Theatre and is open to MRC employees or MRC-funded PhD students at MRC research institutes in Cambridge.

www.eventsforce.net/innovation_afternoon Posters win prizes

Research Councils UK is running a poster competition with a difference for early-career researchers funded by the UK research councils. Perspectives gives researchers the chance to discuss their research with a non-specialist audience, learn about poster design and explore the social and ethical aspects of their work. Finalists will display their poster at the British Science Festival at the University of Surrey in September and cash prizes will be awarded for the best posters. The application deadline is 8 May 2009.

www.britishscienceassociation.org/perspectives Edinburgh Science Festival

Step inside an MRC Laboratory to create a test-tube baby and examine the DNA to see if it’s a boy or a girl. Or hear how researchers discovered a buried treasure of IQ scores that changed the way we think about intelligence in our lives. These are just two of the exciting activities organised and supported by the MRC at this year’s Edinburgh Science Festival which runs from 4 to 18 April 2009.

www.sciencefestival.co.uk Cheltenham Science Festival

The annual celebration of science takes over Cheltenham Town Hall with its trademark blend of debate, scientific stars and hands-on fun in the interactive Discover Zone. This year’s Guest Director is Carol Vorderman and the festival runs from 3 to 7 June 2009.

www.cheltenhamfestivals.com Beyond animal research

Let your imagination run wild to think about novel ways to replace or reduce animals in research. The NC3Rs and New Scientist are holding an essay competition, ‘Beyond animal research’. Entrants should submit a short article on how advances in technology – such as stem cells, tissue engineering or computer modelling - could end the need for animal research. Anyone can apply, but entries are particularly encouraged from undergraduate, postgraduate and post-doctoral scientists and science communicators. The closing date is 17 April 2009.

www.nc3rs.org.uk/page.asp?id=1022

Lord Drayson, Sir David Attenborough and Kate Bellingham at the campaign’s Downing Street launch event.

YOUR

FEEDBACK

MRC Network is for anyone who has an interest in the work of the MRC, including scientists, doctors and health professionals involved in medical research, government departments and parliamentarians, and university staff and students. The aim is to provide a quick, easy- to-read summary of activities across the MRC, from research news through to funding, grant schemes and policy issues, with pointers to more in-depth information on websites and in other publications.

We are very keen to receive feedback on Network and suggestions for new features from our readers. So if you have any comments, please let us know. Just email:

[email protected] MRC Network is produced by the MRC publications team and is available in print and in downloadable pdf format at:

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Latest podcasts

TranslatingresearchintopolicyinScotland

Scottish scientists joined representatives from NHS Health Scotland in December at a meeting designed to promote collaboration and stimulate the translation of scientific findings into government health policy. Hear the views of a scientist and a policymaker who attended the event.

RegenerationresearchwinsNewcombClevelandPrize In February, an MRC-funded research team won a prestigious prize for their discovery of a single molecular cue that promotes limb regeneration in the salamander. One of the scientists talks about this exciting discovery from the 2009 American Association for the Advancement of Science conference in Chicago, where the team received their prize.

To download these and other MRC podcasts, go to:

www.mrc.ac.uk/Newspublications/Podcasts

You can also read the latest MRC news or subscribe to RSS feeds to receive news as it is published at:

www.mrc.ac.uk/Newspublications

BOARD Deadlinedate Board Meeting

Molecular and Cellular Medicine 13 May 2009 20 and 21 October 2009 Infections and Immunity 20 May 2009 28 and 29 October 2009 Populations and Systems Medicine 27 May 2009 4 and 5 November 2009 Neurosciences and Mental Health 3 June 2009 12 and 13 November 2009

STUDENTSHIPS Deadlinedate Panel Meeting Alice Cory Fellowships 27 April 2009 1 June 2009

OPPORTuNITIES