In September 1999, Incyte Pharmaceuticals(Palo Alto, CA, USA) and the HuntsmanCancer Institute (HCI, University of Utah,UT, USA) announced a partnership that couldprovide a huge boost to our understanding ofthe molecular basis of cancer. For the nexttwo years at least, Incyte will provide HCIwith its LifeSeq Gold database of humangenes (Box 1 and Fig. 1) and its system ofmicroarray technology (Box 2) in return forthe HCI’s cancer expertise.

The move towards academic collaborationis a new venture for Incyte. Until now, thecompany offered its genetic databases topharmaceutical companies in return for a fee.The partnership with HCI will be based on anexchange of ideas, technology and expertise,but not cash. ‘We hope that this will providea model for a series of natural academiccollaborations over the next five years,’ saysRandy Scott, Incyte’s President and ChiefScientific Officer. Incyte’s ultimate goal is toform a network of academic partners and,two days after their partnership with HCI wasmade public, the company sent out a call foracademic partners to join their ‘In SilicoPartnership Program’.

The HCI–Incyte partnership was firstmooted when senior research scientists fromPharmacia Upjohn joined the staff of HCI.‘Previous access to Incyte’s databases hadproved so useful that they did not want to

work without it and they initiatednegotiations with us,’ explains Scott.Raymond White of HCI is delighted at theoutcome. ‘We are a fundamentallygenetically oriented cancer researchorganization; we have neither the time northe resources to do large-scale genesequencing; having this resource at ourfingertips will accelerate our researchprogramme.’ White confirms that the twoorganizations intend to work together onmultiple levels. Substantial HCI resourceswill be devoted to the project, which willrapidly become ‘a cornerstone of the cancerinstitute,’ according to White. ‘Our

organizations will share the intellectual rightsto the research findings and we will publishjointly. Although the collaboration is for twoyears in first instance, we expect it tocontinue well beyond that,’ he says.

The first challenge of the partnership isexpected to centre on colon cancer genetics.‘This is a key area because the effectivenessof diagnosis and therapy for colon cancer hasnot advanced greatly during the past 40 yearsdespite extensive effort,’ points out Scott.‘Instead of studying the effects of one or twogenes at a time, we will use microarrays toinvestigate simultaneously all of the 80 000–100 000 genes that have been implicated in

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Cancer researchexplosionimminent

Box 1. Incyte’s LifeSeq Gold database

LifeSeq Gold contains gene expression information for 895 tissue libraries, in both normal and dis-eased systems, and at different developmental stages. It currently contains 4.3 million expressed sequence tags (ESTs), 3.3 million of which are Incyte-proprietary. This represents more than 90% ofall expressed human genes, 50 000 of which are not available in the public domain. Scott predicts that,with the completion of the human genome project in April 2000, ‘expansion of the database to con-tain all expressed human genes will follow by the end of the year.’

Box 2. Gene expression microarray technology

Each of Incyte’s microarrays is tailored to an individual biological system. A library of cDNA mol-ecules containing the genetic information from cells within the chosen system is constructed andthen individual cDNA molecules are isolated and amplified. A micro-sample of each cDNA is thendeposited on a glass surface in an array format with each gene occupying a unique location. Themicro-samples are bonded to the glass; 10 000 unique cDNAs can be assembled in a single array, eachgene 500–5000 bp in length.

When the array is used, large portions from one half of the DNA’s double strands are first re-moved. This process activates the individual elements of the array, preparing them to react and bindto their uniquely matched DNA counterparts in the test cells. In the colon cancer experiments at HCI,cells from different stages of tumour development will be compared to see which genes are expressedat which stage.

mRNA extracted from a normal cell will be used to generate a fluorescence-labelled cDNAprobe that will represent all of the genes expressed in a normal colonocyte. The process will be re-peated for a cancerous cell, but using a differently coloured fluorescent marker. The two fluorescentprobe samples will then be applied simultaneously to a single microarray, to react competitively withthe arrayed cDNA molecules. By reading the pattern of fluorescence, researchers should be able todetermine genes that are expressed in the cancerous cells, but not in normal cells.

Figure 1. Linux processors in one of Incyte’s dataprocessing centers – one of the largest super-computing facilities of its kind for studying bio-logical information.

normal colonocyte development andcarcinogenesis,’ explains White. The HCIteam will begin by using jointly developedmicroarrays to characterize the changes ingene expression in a long-lived colontumour. ‘Colon tumours develop slowly andhave a long intermediate stage – the colonpolyp. We intend to look at cells in variousstages of cancer to identify mutationalderegulation targets,’ explains White.

White believes that there could be twomain pathways that lead to familial coloncancer. The entry point of the first is theadenomatosis polyposis coli gene (APC)(85–90% of all familial cases) and the otheris the hereditary nonpolyposis colorectalcancer (HNPCC) mutator genes (10–15% ofall familial cases). HCI scientists expect todistinguish these two pathways and identifyany others that might exist. ‘If we canidentify which tumours are likely to respondwell to specific chemotherapy and whichdefinitely require radical surgery, thetreatment of individual patients couldbecome more targeted,’ says White.

Although Sir Walter Bodmer (Institute forMolecular Medicine, Oxford, UK) thinks itmore likely that the genes interact at different,very early stages of the same process, hewelcomes news of the collaboration. ‘Thespeed with which we can solve uncertaintieslike this will be a great advantage. I have highregard for the scientists involved in bothorganizations and I think that the extension ofaccess to the LifeSeq Gold database toacademic institutions is a positive step’, hesays. ‘ There is a danger that information willbe generated too quickly – the results willneed to be assessed constantly, so that we canuse them effectively to work out what thefunction of the different genes are and toelucidate the mechanisms by which theyinteract. The plan to involve more academicinstitutions will greatly increase the expertiseavailable to interpret the data that will begenerated.’

Of course, although both parties are fullycommitted and excited by the prospect ofworking together, they recognize that, aswith any collaboration, things can go awry.‘Problems may arise if unexpressedexpectations lead to disappointments or ifunexpected ethical issues develop,’ saysWhite. And everyone is aware that, althoughthere is tremendous potential, the work willnot be easy. ‘There are a finite number ofgenes in the jigsaw puzzle that is the humangenome; by the end of the year 2000 we willhave all the pieces out of the box and will beable to see them. But fitting the first pieces ofthe puzzle together will be hard and it willtake time,’ warns Scott.

Kathryn SeniorFreelance science writer

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Doctors diagnose most cases of type 1diabetes mellitus only when symptomsemerge, which is usually before the age of30. However, a genetic screening programbeing evaluated at the University of Florida(Gainesville, FL, USA) aims to identify high-risk neonates. In the future, researchers hopethat early identification will allow them tointervene before the autoimmune responsedestroys insulin-producing b-cells.

The ‘prospective assessment in newbornsfor diabetes autoimmunity’ (PANDA) studyhas screened more than 4000 babies over thepast two years to assess genetic susceptibilityto type 1 diabetes. Now backed by a newUS$ 2 million National Institutes of Healthgrant, researchers plan to test another 8000neonates and track genetically high-riskbabies to discover the impact of possibleenvironmental triggers, such as breastfeeding, immunizations and viral infections.

Currently, however, these environmentaltriggers remain enigmatic. ‘Whatever it is, webelieve it occurs very early in life,’ saidDesmond Schatz, Professor of PaediatricEndocrinology at the University of Florida’sCollege of Medicine. ‘If we learn whatcauses the disease, then we can find a betterway to stop it in its tracks or prevent italtogether.’ In the meantime, knowing that achild is at high risk allows parents to follow,for example, healthy eating guidelines.

A growing body of evidence implicatesgenetics as a factor in susceptibility to type 1diabetes. ‘People who have a close relativewith type 1 diabetes have a higher risk ofgetting it than the general population – abouta 1:20 chance compared with 1:300,’ saysgeneticist Jin-Xiong She (University ofFlorida, Gainesville, FL, USA). ‘But about90% of the people who have the disease donot have a close relative who also has type 1diabetes. So most people don’t expect the testto show the high-risk genes.’

Dr She explains that perhaps between 15and 20 genes contribute to the risk ofdeveloping type 1 diabetes. But geneticistshave identified only a few of these, localizedmainly in the HLA-D locus on chromosome 6and the insulin gene region on chromosome 11.The University of Florida programme screensfor two susceptibility genes, HLA-DRB1 andHLA-DQB1. ‘The genetic test’s predictivepower is pretty good,’ adds Dr She. Thesegenes allow the researchers to identify 70–80%of those at risk of developing type 1 diabetes.

Dr She stresses that any interventions willprobably only prove effective if they areinitiated before the emergence ofautoantibodies. This means that neonatesmust be screened (Fig. 1). Based ongenotyping and family history, researchersstratify infants according to their expectedrisk of progressing to type 1 diabetes, whichcan be anything from 1:4 to 1:15 000(although the latter suggests protection fromthe disease). ‘We will not only identify high-risk patients, but also those with theprotective genotype,’ he notes. ‘By looking atthe genetic information, we’re trying to movethe entire study of prevention to a muchearlier stage, to try to understand who willdevelop the autoantibodies.’

Another ongoing study examines changesin gene expression as the disease progresses.Dr She hopes that molecular markersrevealed in this study might yield new drugtargets that block upregulation of the criticalgenes. The researchers are also storing DNAsamples in case other genetic markers emergein further studies.

However, the team’s focus over the nextfew years will be on identifying possibleenvironmental factors. ‘There’s not enoughdata yet. The prospective study should give adefinitive answer,’ She concludes. ‘But it’llbe another three to four years before we havethe results.’

Mark GreenerFreelance science writer

PANDA identifies babies atrisk of developing type 1diabetes

Figure 1. A medical lab assistant at ShandsHospital at the University of Florida places a dropof blood drawn from a neonate’s foot on a testcard to screen for diabetes risk. Photograph byRossana Passaniti, University of Florida,Gainesville, FL, USA.