KING'S COLLEGE, LONDON

Professor Frederic Geissmann and Professor Andrew Cope

Top Guys at King'sThe two new arc professors at King's College, London, talkto Arthritis Today about their new roles - and their excitingplans for future research.

There's nothing modest about Andy Copeand Frederic Geissmann's ambitions.

The pair, both newly appointed as ArthritisResearch Campaign professors at King'sCollege London (KCL), have big plans forthe future of research into inflammatoryforms of arthritis. In a nutshell, bycombining their clinical and scientificexpertise, they are planning new ways oftackling inflammation that could lead toimproved treatment-and even preventinflammatory disease from happening inthe first place.

With a £4.1m endowment from arc andinput of £2.6m from KCL and Guy's andSt Thomas' charity, a new research centreis being constructed at the heart of theGuy's campus where a large group ofscientists and clinicians will collaborate ina multidisciplinary programme of researchon inflammation and inflammatorydiseases.

The new Centre for Molecular and CellularBiology of Inflammation is opening in aphased way through the year, and shouldbe fully up and running towards the endof 2009.

Frederic Geissmann, a world authority onimmune cells called phagocytes, was lured

to KCL with the promise of funding andfreedom to pursue his research interests.With his impressive CV and research trackrecord, new colleague Andy Cope describeshim as a "superstar".

A stimulating environmentProfessor Cope in his turn could hardlyresist the offer of being a part of thisnew centre from its inception, leavinghis long-time base of the arc KennedyInstitute of Rheumatology for the promiseof new opportunities for making importantcontributions to arthritis research.Showing visitors around the fledgling unit,both men are openly excited about theopportunities that the centre offers themand their team of up to 70 researchers. Itwill provide a stimulating environment forthe next generation of trainee scientistsand clinicians, including the PhD studentssoon to be recruited as part of the OliverBird Rheumatism Programme.

They are also keen to stress that the twoof them are very much a package. It's thefirst time that two arc professors have beenappointed at a single institution; FredericGeissmann as professor of inflammationbiology, Andy Cope as professor ofrheumatology. They fill a post left vacant

FOCUS ONKING'S

COLLEGE,LONDON

since the retirement of previous incumbentProfessor Gabriel Panayi a few years ago.

Andy Cope explains the reasoning behindthis: "If you were to go back 20-30 years,senior academics served multiple roles,being responsible for the clinical serviceand at the same time running a laboratorydedicated to clinical or basic research. Thiswould involve significant administrativeduties in the hospital and universitysetting, and a big commitment to teachingand training. It was a challenging job, evenback then. The landscape has changedin recent years with growing pressureson clinical service delivery and a highlycompetitive research environment. Thishas made it very difficult for a clinicianto make major contributions in clinicalmedicine and in the laboratory. In fact,clinical and laboratory-based career pathsin medicine have diverged, and so inrecent years it has become increasinglydifficult for universities to recruitindividuals who can deliver excellencein all three domains - clinical service,research and teaching."

A great opportunityFrederic Geissmann adds: "This is notonly about spreading responsibilities orworkload. Over the past 30 years, sciencehas become a major force that has drivenprogress in clinical medicine, and there isa real opportunity today to build a betterclinical medicine based on an in depthknowledge of the precise, molecular,mechanisms of diseases. However, onlyrelatively few universities in the world havethe will and means to lead this process.So when Adrian Hayday, chairman of theDivision of Immunology, Infection andInflammatory Disease (which includes theacademic department of rheumatology)at KCL, told me that that Professor AlanSilman, the medical director of arc, andKCL were keen to give financial supportto create a basic science centre workingon the mechanisms of inflammation- that would work together with therheumatology department to improve ourunderstanding of chronic inflammatorydiseases, and to develop new diagnostic

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KING'S COLLEGE, LONDON

markers and better treatments -1 decidedit was a great opportunity for me, and Iaccepted to be the head of this centre."

There are obvious synergies between thenew professors. Professor Cope has beeninterested for many years in understandinghow the immune system, in particularthe T lymphocyte, becomes activatedin inflammatory disease, and why thejoint becomes the focus of this activityin patients with arthritis. Monocytesandmacrophages, the cells whose functionis the focus of Professor Geissmann'sresearch, play a central role in immuneactivation and are likely to drive theinflammatory process that attracts T-cellsand other cell types to joint tissues duringthe very early stages of disease.

Working towards the 'HolyGrail'Another of Professor Cope's clinicalresearch interests focuses on what hebelieves is the 'Holy Grail' for researchersand clinicians working in rheumatoidarthritis research - identifying healthypeople in the community who are mostat risk of developing the condition - andactually then being able to carry outstudies that might even prevent RA in thefirst place.

"The research groups that have made thebiggest impact on patient care have beenthose who have invested in building uplarge cohorts of patients," explains AndyCope. "A cohort is a large collection ofpatients with the same or closely relateddisease. By capturing detailed informationfrom patients and comparing this withdata from healthy control subjects youcan learn a lot about the disease at thepopulation level."

Andrew Cope withTharsana Tharmalingam (research technician) centre andDr Joanna Clark (senior postdoctoral research fellow) right

"The question we now want to ask how is:can we establish a cohort of apparentlyhealthy individuals who are at high riskof developing RA? This would be a greatopportunity to study the interactionsbetween genes, environmental factors,and the immune system, and how theyinteract to cause disease."

Treating the high risk groupwith cheaper, safer drugsWith collaborators at the arc epidemiologyunit in Manchester and at ImperialCollege, Professor Cope is setting upthe first stage, looking to recruit asubstantial cohort of subjects at high riskof developing RA-for example womensmokers, who may be overweight, andalso carry the genes associated withsusceptibility for RA. The team will thenwatch these individuals very closely to seeif they go on to develop the disease, andcompare the results from a low risk cohort

of the same gender and agebut who don't carrythe susceptibilitygenes. Cope believesthat the populationin south east Londonis an ideal settingfor such studies.The ultimate goalwould be to treat thehigh risk group withcheaper and saferdrugs before showingsigns and symptomsof the disease andso prevent it fromoccurring.

Professor Geissmann has already gainedvaluable new insights into the vital rolethat phagocytes play in the inflammatoryresponse to disease. These cells patrol ourbody in the bloodstream and move intoinfected tissues when required, engulfinginvading microbes and secreting chemicalsthat stimulate other immune cells andcause inflammation. How do they do thisand why don't they stop doing this inarthritis?

To answer these questions, ProfessorGeissmann has developed a noveltechnique that reveals cell behaviour ina totally new way. The cells are made tofluoresce so that they glow when viewedunder a powerful microscope, and areviewed in real time, in living tissue. Theimages are fascinating-the cells can beseen as blobs of colour moving around thetissues and interacting with other cells.

Cutting edge imaging"The methods we use to investigate thecells are technically very demanding," saysProfessor Geissmann, "and that's why it'sso important to have good collaborationwith our imaging department specialists.We're using cutting edge imaging and celltargeting techniques that allow us notonly to view the cells but to investigatehow their development and actions arecontrolled."

Advanced imaging is also generating newknowledge at the molecular level as well.Within immune cells, genetic materialis responsible for programming themanufacture of inflammation chemicals,such as tumour necrosis factor (TNF) andother cytokines. Understanding this controlis crucial to inflammation research.

KING'S COLLEGE, LONDON

Professor Geissmann explains: "We wantto find out which genes are responsibleand how they affect the metabolicpathways that start and stop cytokinemanufacture after infection. In arthritis,cytokine production is excessive andsustained. We may be able to designtherapies that interrupt or stimulate therelevant pathways to prevent this. Thegoal is to correct the imbalance withoutcompromising the body's ability to fightinfection."

The role of the humble fruitfly, DrosophilaThe research model for these studies isthe humble fruit fly, Drosophila. This mayseem a surprising model but in fact thegenes responsible for cytokine productionin the fly are similar to those in the human- over 90 per cent of our genetic materialis the same - and the research willeventually translate into human studies.The fly is a very convenient experimentalmodel - easy to reproduce quickly inlarge numbers and without the ethicalconstraints of rodent models.

The relevant Drosophila genes are tagged

with fluorescent proteins so that oncethey are activated, the fluorescence canbe tracked using advanced imagingtechniques able to monitor living systems,and the images are simply stunning.

Christine Wong and Celine Trouillet,PhD student and laboratory managerrespectively, have been establishingthis novel technique and preparing thegenetic material in preparation for thestudies: "We can't wait to move intothe new research centre facilities. Thenew laboratory facilities have beenpurpose-built to our particular researchspecifications and will make a hugedifference to our operational ability andthroughput."

Mapping the outcomes ofthe immune responseThe flies will be infected with microbes tostimulate an immune response and theresulting gene activity tracked in real time."We already know," says Christine Wong,"that the genes responsible are active inthe joints in humans and interestingly,this has been found to be the case inDrosophila too. We are going to study each

Frederic Geissmann with Celine Trouillet andChristine Wong

gene in turn and map the outcomes of theimmune response for each one."

Professor Geissmann agrees: "Duringinfection the body fights to restore health,and the cytokine system relies on a finely-tuned control mechanism. We'll investigatehow this control is achieved, why the jointis a focus of activity, and potential avenuesfor manipulating the system to blockexcessive inflammation in arthritis. Theanalysis will be challenging, but we shouldachieve the first detailed genetic blueprintof inflammation control in Drosophila - aworld first."