Drug Companies on Speed

Bioinformatics may also be the only way drug companies can deal with the gigabytes of data they produce and receive every day. The pharmaceutical trade organisation Pharma-ceutical Research and Manufacturers of America predicts that by 2003, scientists will have discovered more than 10,000 potential targets for drug development, resulting in what some call "target glut" And that number will only get larger thanks to the 30,000 genes and an exponentially greater number of proteins being identified and analysed in the Human Genome Project. At the same time, combinatorial chemistry allows companies to synthesise more than 100 compounds per chemist per year. "Informatics is how you deal with the amount of data being generated,"says Rick Roberts, global head of discovery research informatics for Pfizer.

In the past five years, most big drug companies have created official informatics departments, either by integrating their research and IT departments or by creating close ties between the two. But the unofficial origins go back further. "It started as an outgrowth of the scientific discipline as opposed to IT,"says Nathan Siemers, group leader of bioinformatics at New York City-based Bristol-Myers Squibb. "Basically it's been a research endeavour, but over its evolution it's become more infrastructure-related. More people need access to this information, and the scale of information we have to disseminate to our clients - the researchers - is growing drastically. So our ties to IT, which originally were almost non-existent, have become stronger and stronger."

Today, there are informatics technologies popping up to help at nearly every stage of the drug development process. Early on in the process, bioinformatics technology allows researchers to analyse the terabytes of data being produced by the Human Genome Project. Gene sequence databases, gene expression databases (which track how genes react to various stimuli), protein sequence databases and related analysis tools all help scientists determine whether and how a particular molecule is directly involved in a disease process. That, in turn, helps them find new and better drug targets.

Using IT analysis tools and genomic databases, for example, Merck researchers were able to compare the entire genome sequence for mice and humans. They not only discovered that the two genomes were 90 per cent identical, but they also found a gene in mice that might have the same function as a gene that may be involved in schizophrenia in humans, says Richard Blevins, who has been Merck's director of bioinformatics for three years. Currently Merck is working with genetically altered, or "knock-out", mice, in which certain genes are altered to create a specific mutation (schizophrenia, in this case) to see how the animals react to drug candidates. This research, still in the very early stages, could eventually lead to a target for a new schizophrenia drug, Blevins says.

Similarly, Bristol-Myers Squibb has discovered a novel method for treating epilepsy using gene-sequencing mining tools. The particular drug candidate isolated for this research has since shown strong efficacy in knock-out mice and is nearing clinical trials, according to Siemers of Bristol-Myers Squibb.

Drug companies also employ a variety of cheminformatics software - tools that can predict the activity of a particular compound by studying its molecular structure. For instance, scientists can use molecular modelling software (tools that rely on interactive 3-D visualisation or mathematical algorithms) to discover and design safe and effective compounds. Chemical databases allow researchers to store and retrieve compounds and related data. Robotics makes it possible for chemists to synthesise hundreds of thousands of chemical compound variations from a library of simpler molecules in a short amount of time. High-throughput screening technology (see "The Definitions of Life", page 121 ) allows researchers to screen thousands of compounds at once, rather than just 10 or 20.

Technology may help at the clinical testing stage too, though it has been a bit slower to catch on. Virtual patient simulation software, like the Asthma PhysioLab program that showcased virtual patients Alan and Bill, can simulate patients, targets and therapies in order to predict experimental outcomes before companies commit major resources to lab research and clinical trials. Essentially, this software helps predict the effect particular compounds have on the human body.

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Sharing the knowledge gleaned from these new informatics tools is as important as integrating the technologies themselves. With their geographically dispersed personnel, most large pharmaceutical companies have found that the Web is the best tool for that data dissemination, and they are housing most of their informatics tools and data on intranets.

Merck Company, which first took advantage of the Web and its intranet in 1995 to begin sharing bioinformatics data across its four research facilities located in New Jersey, Pennsylvania, Canada and the UK, now inputs changes to 150 genomics- and proteomics-related databases every night. The company shares 10 terabytes of data among 1000 scientists around the globe. "We have to make sure they're up to date and that wherever you are at Merck, you see the same data,"Blevins explains. "That's something."

New York City-based Bristol-Myers Squibb also uses its intranet to house most of its bioinformatics applications. IT professionals and scientists there have created a portal called GeneTracker on its intranet that makes it possible to share gene sequence, gene expression, scientific literature and links to more sources of bioinformatics data among the company's four US research locations.

And New York City-based Pfizer and UK-based GlaxoSmithKline are experimenting with grid computing, a new initiative that involves harnessing extra computer processing power in order to share huge database files and applications across high-speed networks. Grid computing, some say, will give pharmaceutical companies even more computing power than is currently available.

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The chief challenge for CIOs is piecing together all those diverse technologies into a fully integrated drug discovery process. Given that hundreds of vendors are jumping on the bioinformatics bandwagon and there are very few standards, that is no small feat. "RD chiefs and CIOs are looking at all of these immature technologies in a quickly evolving marketplace and are being forced to spend quickly,"explains Craig Wheeler, vice president of Boston Consulting Group. "But it's necessary to put it all together - in silico [in the computer], in vitro [in test tubes] and in vivo [in life] - to get any real value out of it."

In order to do that, they've had to call in the IT troops, which have long been isolated from the lab scientists. Whether as a part of a new informatics department or working hand in hand with research, the role of IT is becoming increasingly important in the pharmaceutical industry. Peter Loupos, Aventis's vice president of drug innovation and approval information solutions, studied molecular biology and genetics as an undergraduate and IT as a graduate student. He now sits on the leadership team for drug discovery at Aventis and has watched the role of IT evolve.

Just five years ago, IS was a relatively isolated department responsible for providing infrastructure and operational support at Aventis. Today, the company's far-flung research teams depend on sophisticated software and hardware to do their jobs. The early phases of drug development are often done in silico, Loupos notes. "Similarly, it is impossible to perform global clinical trials and prepare [Food and Drug Administration] submissions unless the process is implemented with an e-business philosophy. This means that as an organisation we had to change our strategy, our focus and our skills,"he adds.

The role of IT is now central to successful research and development at Aventis. "This visibility has moved the organisation from the background to full partnership,"Loupos says. Aventis now employs "a cross-functional team approach, bringing together the skill sets of scientists, informaticians and IS professionals to create new solutions to drug discovery."

At Merck, the 30-person bioinformatics group is one-third computer scientists, one-third natural scientists and one-third that rare breed - the bioinformatician - with a dual background in science and IT. "To do [informatics] correctly you need to blend scientific skills and IT skills. Many on our staff are scientists with strong IT backgrounds,"Pfizer's Roberts says. "Otherwise you get technology without a purpose."

That partnership is particularly vital because most pharmaceutical companies are doing a combination of building some tools in-house, licensing software, and partnering with or buying up companies that already have a piece of the technology. The main reason for these acquisitions is that most can't find enough qualified individuals to keep up with their demand for new tools, and their core business remains drug, not software, development. "Our internal resources don't come close to matching our demand for tools,"says Ken Fasman, vice president and global head of research and development informatics at Massachusetts-based pharmaceutical company AstraZeneca. Fasman oversees a staff of 55 worldwide.

In 1998, Bristol-Myers Squibb built its own Laboratory Information Management System (LIMS), a database that allows the company to track DNA samples as they are sequenced, stored and analysed by scores of different scientists. The choice to build rather than buy at that time was out of necessity. "None of the vendors offered the kind of flexibility we needed,"Siemers explains. He needed a system that could be easily accessed by a scientist who was working at the bench with only three samples as well as by researchers examining 30,000 samples with a high-throughput screening device.

Although that LIMS is still in use at Bristol-Myers Squibb, the preference now is to buy informatics software and integrate it into the company's custom-built systems. "Our philosophy is if we can find a tool from a vendor that will do the task, it's in our interest to just go out and buy it,"Siemers says. "Our business is drug development, not software engineering."

But hundreds of vendors in the informatics space combined with varying standards and platforms makes the integration task tricky. Even Pfizer, known for doing more informatics in-house than most, works with about 15 major vendors in this area. "It's really become an integration job, and it's very difficult,"Roberts says. At Pfizer, Roberts uses simulation software from Missouri-based Tripos, chemical databases from California-based MDL Information Systems, and screening and visualisation tools from Massachusetts-based Spotfire, just to name a few. "We work very closely with all of our partners and try to sway them to build to our standards,"he says. "But frankly none of these systems are perfect, and we have to build a lot of bridges."

For example, Pfizer's scientists often use one database to examine the chemical structures of compounds in order to make assessments about their viability as drug targets. And then they have to transfer that information into a completely different piece of software from another vendor to assess that molecule's biological properties or safety. As a result, Roberts and his department are constantly faced with the challenge of building application programming interfaces (APIs) between different systems and databases.

Although vendors are beginning to offer more modular systems that can plug in to other systems or well-documented APIs in an effort to garner a bigger chunk of this billion-dollar business, many are still hawking closed, standalone systems. "We're able to push vendors more and more to work with open standards, but when someone has a monopoly position, you don't have a lot of leverage,"says AstraZeneca's Fasman, who works closely with his IS counterparts to deal with such problems.

The number of mergers and acquisitions in the drug industry further complicates the integration issue. Recent major drug marriages include Warner-Lambert with Pfizer, and SmithKline Beecham with Glaxo Wellcome to produce the Middlesex, England-based GlaxoSmithKline. "Everyone has different databases,"says Dinerstein of Aventis, which was formed by the merger of Hoechst Marion Roussel with Rhone-Poulenc Rorer in 1999. "We have immense amounts of data, but our first task is to figure out how to make that data accessible."

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DNA sequence: The sequence of nucleotides in DNA, the molecules that control all hereditary characteristics.

Gene: A hereditary unit consisting of a sequence of DNA that occupies a specific location on a chromosome and determines a particular characteristic in an organism.

Gene expression: The process by which a gene's coded information is converted into proteins and other molecules carrying out crucial activity within the cell.

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