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DNA and BioChips: 1
DNA and BioChips: 1
THE MAKING OF A MICROARRAY

When prepared properly, DNA chips and microarrays permit researchers to gather more data in less time. Here's a guide to the steps in making chips and the products that simplify the process.

BY PETER GWYNNE AND GARY HEEBNER



ADVERTISERS
Agilent Technologies
www.agilent.com/chem/labchip

American Society for Biochemistry and Molecular Biology
www.asbmb.org

American Type
Culture Collection
www.atcc.org

Ciphergen
Biosystems, Inc.
www.ciphergen.com

GeneMachines, Inc.
www.genemachines.com

Idaho Technology
www.idahotech.com

Lab Products, Inc.
www.labproductsinc.com

LION Bioscience, AG [Germany]
www.lionbioscience.com

LION Bioscience [USA]

Nanogen, Inc.
www.nanogen.com

Packard Biochip Technologies
www.packardbioscience.com

Sequenom, Inc.
www.sequenom.com

CONTENTS
An Expanding Business
The Big Bottleneck
Two Types of Chips
Oligos' Emergence
The Basic Steps
Preparation Kits
Onto the Chip
Labeling, Scanning, and Handling Data
From Gene Expression to SNPs
Strategy for SNPs
This is the first of a two-part series. The second part, which will focus on protein microarrays and lab-on-a-chip technologies, will appear in the 10 May 2002 issue of Science.

The companies in this article were selected at random. Their inclusion in this article does not indicate endorsement by either AAAS or Science, nor is it meant to imply that their products or services are superior to those of other companies.

In just over a decade since their conception, DNA chips and microarrays have proven their value in genomics research and have forever changed the way in which molecular biologists approach their research. The rush to capitalize on information produced by the sequencing of the human genome is well under way, with researchers from many disciplines already acknowledging the power of these miniature laboratories on a slide. These early adopters have begun to reap the basic benefits from DNA microarrays: more data in less time.

DNA chips and microarrays allow the simultaneous examination of thousands of strands of DNA. At times, indeed, they create overpowering amounts of data. Thus the utility of these new laboratory tools depends on strong support from information technology. Fortunately advances in that sector have enabled the development of the powerful computer software programs necessary to make sense of such large volumes of data.

AN EXPANDING BUSINESS

Backed up by suitable software, DNA microarrays have clearly become extremely valuable research tools. As such, they play a key role in gene discovery, disease diagnosis, and drug discovery. "This is one of the handful of technologies that are applicable in the entire scope of R&D, from drug discovery through development," says Keith Dionne, vice president and general manager of technology business for Millennium Pharmaceuticals, Inc.

Potential users see huge promise in the technology. "The microarray market is not mature yet," says Siobhan Pickett, product line manager, array technology for Axon Instruments, Inc. "What's happening is that the early adopters and innovators are now moving into a mature phase in which they have the technology that's helping them to move forward to the next stages of their research. The market will grow in the near future as microarrays become a much more standardized technology in many types of life science laboratory, like gel electrophoresis and DNA sequencing."

The market already appeals to a broad range of consumers. "We originally assumed that our customers would be predominantly in the biopharmaceutical area," says Doug Amorese, section manager for biochemistry and chemistry in Agilent Technologies, Inc.'s Bio Research Solutions division. "We've been very pleasantly surprised by the demand in the academic and agricultural areas. This technology is being used across the board as it has matured to deliver lower costs and better product offerings."

John Burzcak, vice president for development of genomics at Amersham Biosciences (formerly Amersham Pharmacia Biotech), echoes that thought. "Pharmaceutical and life science companies have strongly embraced microarray technology," he says. "In the academic environment, microarray capabilities have been established in core laboratories that service individual investigators. As the technology matures, investigators' laboratories are clearly purchasing the tools for postspotting work, such as microarray hybridization reagents, kits, and instruments, as well as microarray scanners."

Further development of microarraying, and particularly of methods for interpreting the information that the method produces, will expand the technology's utility. "Now that the technique is developed you can optimize it," explains Horst Donner, head of R&D microarrays at German firm MWG Biotech AG. "However, it's not the technology but making sense of the data that will open the way to more use of microarrays. I'm convinced that the technology will soon find clinical applications."

THE BIG BOTTLENECK

Dealing with data has emerged as the key issue for vendors and users of DNA microarray technology. "The data analysis portion of a microarray experiment can in many ways be the most challenging part," says John Quakenbush, an associate investigator at The Institute for Genomic Research (TIGR). "The big bottleneck in microarray work is data analysis — the ability to assign quality and statistically analyze a massive amount of data from multiple slides and experimental conditions," adds Burzcak of Amersham Biosciences. "'Power users' such as pharmaceutical companies have created bioinformatic departments to service investigators. And as academic investigators push into analysis of large data sets, they may require core bioinformatic services."

Another factor essential to expansion of the industry is standardization of bioinformatics and many other aspects of microarray technology. Vendors of microarray systems and components face a situation similar to that encountered by computer companies 20 years ago, when they decided to move away from proprietary technologies to open systems. "The needs and interests of the scientific community will drive standardization," says Axon's Pickett. "But they are also looking for guidelines from the product suppliers. So the most successful standards will result from collaborative efforts between companies such as Axon and their customers."

Already Affymetrix, Inc., and Molecular Dynamics, a division of Amersham Biosciences, have formed the Genetic Analysis Technology Consortium (GATC). Its goal: to standardize array based genetic analysis, thereby paving the way for the more affordable and productive development of products for therapeutics, diagnostics, and disease management. It plans to do so by agreeing on a unified technology platform to design, process, read, and analyze DNA arrays. Researchers should benefit as GATC-compliant probe arrays, readers, reagents, and software and database architectures will eliminate the need for redundant equipment and software.

Few companies in the DNA chip business offer complete systems for working with DNA chips. Rather, most have focused on specific areas of technology and offer a limited range of products. Although this helps the companies to master their respective arts, it poses problems for researchers who need to assemble the pieces in their laboratories. Two notable exceptions are market pioneer Affymetrix and Agilent, which recently introduced a complete solution from arrays and labeling reagents to scanner and analysis software.

In addition, several companies have recently decided to work together to offer bundles of compatible microarray products. GeneMachines, a vendor of DNA synthesizers, microarray printers, and pens for spotting microarrays, provides an example. "We work very closely with several scanner manufacturers," says president and CEO Scott Hunicke-Smith. "We believe the market wants one-stop shopping, including the bioinformatics software needed to interpret microarray data."

TWO TYPES OF CHIPS

The terms DNA chip and microarray are often used interchangeably. Strictly speaking, chips (or macroarrays) usually have a lower density of spots or features per unit area while microarrays have a higher density. In fact, microarrays can contain as many as several hundred thousand spots per slide. DNA is not the only raw material for biochips. Other types under development and in research laboratories include protein chips, antibody chips, and other lab-on-a-chip devices that are the result of miniaturization efforts. This article will focus exclusively on DNA chips and microarrays.

The two basic types of DNA chips are differentiated by their method of production. One involves synthesizing oligonucleotides on a chip. The second spots presynthesized DNA (amplicons or oligonucleotides) onto a chip or glass slide.

Affymetrix originally developed oligonucleotide arrays by synthesizing oligonucleotides on a wafer or chip using a patented method for manufacturing integrated circuit chips borrowed from the semiconductor industry. The process involves using photolithography to add nucleic acid bases selectively to predetermined spots on the chip. This process enables the in situ (on a slide) creation of oligonucleotides up to 20 or so bases in length. This approach has one main disadvantage: high cost. Producing such a mask requires a substantial financial investment. Further, photolithographic masks cannot be altered to produce arrays with different oligos without incurring further cost.

Agilent has developed an alternative method. Exploiting its technological heritage, the company uses inkjets to deliver traditional phosphoramides and activaters to discrete locations on a modified glass support. By using traditional chemistries with high coupling efficiencies, Agilent can offer arrays of oligos 60 nucleotides in length by an in situ process.

With its series of GeneChip products, Affymetrix is one of several companies that cater to researchers who do not wish to master the art of making their own chips. Other firms offering DNA microarrays ready to use for popular applications include Clontech Laboratories and Azign Bioscience A/S (formerly Display Systems Biotech), whose discoverARRAY slides have over 2,400 expressed fragments of complementary DNA (cDNA). Mergen Ltd. also provides such arrays.

A second method of producing a DNA chip involves spotting DNA (again amplicons or oligonucleotides) onto a slide. Users can obtain the cDNA from libraries or produce it from the mRNA (messenger RNA) of a cell. Pat Brown of Stanford University pioneered this process. The Brown laboratory has gained a worldwide reputation for its promotion of DNA chips. Its website features a wealth of information on how to make and use DNA chips.

Producing a cDNA chip requires an intermediate step that Affymetrix's production method doesn't need: the use of reverse transcriptase polymerase to generate a library and the polymerase chain reaction (PCR) to convert cDNA into an amplicon. In recent years the polymerase chain reaction and reverse transcriptase have advanced from art to science, largely owing to the efforts of several companies to create more reliable ways of amplifying nucleic acids. Suppliers such as Amersham Biosciences, Invitrogen, Promega, QIAGEN, and Stratagene have developed kits and complete systems that have taken much of the trial and error out of amplifying DNA or RNA. "For individuals who don't want to make their own PCR products we offer ready-to-spot human PCRs," says Becky Mullinax, senior staff scientist at Stratagene. "We'll do the same for mouse PCRs in the middle of this year."

OLIGOS' EMERGENCE

The oligo approach is undergoing development as vendors develop new methods of depositing oligonucleotides. Thus QIAGEN Operon, a fully-owned subsidiary of QIAGEN, offers custom oligonucleotides in amounts, concentrations, and plate formats specified by customers. "QIAGEN Operon produces oligos that can be spotted," says Martin Potgeter, QIAGEN's strategic marketing manager for array systems. "We can offer selected oligos for genes. We have an oligo center with more than 50,000 human genes so that people can pick and spot their own." Agilent also prepares custom arrays. "We have software tools that allow one to design probes to nearly any length," says Amorese. "The probe sequences are converted into a design file for our in situ writer; then we can produce an array — as a single one or in the thousands — by synthesizing on a single base at a time at all locations on the array in parallel."

MWG-Biotech AG focuses on synthesizing oligos first and coupling them to the substrate surface afterward. "The main disadvantage of Affymetrix's on-chip synthesis is the limitation in the length of the oligos," says Donner. "We can purify the oligos and check them prior to spotting, which isn't possible with on-chip synthesis."

Different oligo makers provide the market with a choice among the lengths of oligos available for purchase. Some vendors regard the 20-mer length of Affymetrix's oligos as too limiting. "We use 50-mers," says Donner. Why? "It's a matter of production," he explains. "Our mass spectrometry can check oligos only up to 50-mers. And tests we have carried out suggest that 50-mers are highly specific, while oligos with more than 50 base pairs can lead to cross-hybridization."

QIAGEN Operon has a different take on the issue. "We have decided to use 70-mers and one oligo per gene," says Potgeter. "They are more selective. And scientists like to see the message coming from the tissue. The role of Operon is to support our customized chips with longer oligos." Agilent splits the difference. "We typically use 60-mer oligos rather than the shorter ones," says Amorese.

Whatever the selected length, it's clear that customers have increasingly opted for oligo arrays in recent months. "There's a move away from cDNAs to long oligos," says TIGR's Quakenbush. "I see an evolution toward these long oligos to ease sample handling. Complementary DNAs are hard to work with over a long period of time. Oligos are easy to maintain and reproduce. The challenge of using long oligos is that you rely on having a good working knowledge of what the genes are."

Millennium, which up to now has largely made and used its own cDNA arrays with nylon substrates, has recently started to take the oligo route. "We are substantially ramping up our use of Affymetrix microarrays," says Dionne. He cites three reasons for the change. "First," he says, "we think the Affymetrix platform has improved to the point at which it rivals our nylon platform. Second, the oligo base will have significant advantages in terms of giving us the ability to query certain parts of the genome that cDNAs can't query. And third, it gives us the opportunity to shift our resources downstream because we don't have to produce our own arrays."

THE BASIC STEPS

Whatever the form of DNA, producing and conducting experiments with DNA chips requires several basic steps. "You can't just take a PCR product or genomic DNA, put it on a microarray and obtain a nice signal," says Michael Pirrung, professor of chemistry at Duke University. "Once the chip is in hand you have to have a sample preparation step." His group has developed its own method of preparation, referred to as optical scissors. "We use a photochemical approach," he explains. "The technique can make single-stranded products or directly make short fragments for the microarray. It's a research problem at this stage. We're making a number of modified nucleotides."

In general, any scientific group must prepare or purchase a slide or chip, synthesize or obtain the DNA, apply the DNA samples to the chip, conduct a hybridization experiment with a sample of interest, scan the chip, and analyze the data. Several suppliers have entered the DNA chip market recently, providing the tools needed to produce chips as well as ready-to-use chips for popular applications.

DNA is attached to a solid substrate, such as a silicon/ceramic wafer, glass microscope slide, or a nylon membrane. Some of the early work with glass microscope slides was complicated by the fact that glass slides required pretreatment with such chemicals as polylysine to prepare the surface for DNA attachment. Those slides had poor lot-to-lot consistency. However, it did not take long for suppliers to develop better performing products. Corning, Inc., quickly introduced its CMT-GAPS aminosilanized slides. These offered lower background noise and better consistency. Corning has recently left the microarray business. However, other companies offering the latest in prepared slides for DNA chip production include Clontech, Genpak (a part of British company Genetix Group PLC), and Schleicher & Schuell.

Quakenbush at TIGR has successfully used super amine slides. "We are also getting away from harsh chemical treatments," he says. "I've been told that we make the best arrays that people have seen."

For genomic research, the entire genome of an organism is extracted from cells or tissue. Gene expression studies need either total RNA or mRNA for DNA synthesis. The purity of RNA is a critical factor in the hybridization step when labeling with fluorescent tags. Proteins or other contaminants can promote significant nonspecific binding to the slide's surface of fluorescent-labeled target DNA.

PREPARATION KITS

As in the case of many molecular biology techniques, suppliers have come to the aid of scientists by offering kits designed to simplify the preparation of DNA samples. Companies that produce reagents and kits for isolating and purifying DNA include Brinkmann (an Eppendorf company), Clontech, Millipore, and Promega. "We have three different RNA preparation kits for microarrays," says Mullinax of Stratagene. "We have a mini-, micro-, and nanokit. The difference is in the number of cells that the kit can deal with: 105 to107 for the mini, one to 105 for the micro, and one cell to 104 for the nanokit. We're recommending the micro- and nanokits for customers doing laser capture microscopy."

A few companies focus almost exclusively on providing tools for this segment of microarray manufacture. QIAGEN offers a broad range of reagents and kits for isolating and purifying DNA and RNA. "The better the preparation, the better the results," says Potgeter. "Your RNA has to be intact. Hence we have a program of RNA stabilization. One of our products is RNeasy Protect for tissues." In a recent collaboration with BD Biosciences, QIAGEN has developed a method of collecting blood and stabilizing it in a container. "We try to avoid any destruction of RNA — not just to get rid of shortened strands but also to avoid instability from RNA lying around for a long time," Potgeter continues.

Alternatively, scientists can buy oligonucleotides from companies such as MWG-Biotech, QIAGEN Operon, and Sigma Genosys. These suppliers provide custom oligonucleotide synthesis services. "We deliver catalog microarrays premanufactured," says MWG's Donner. "We also offer custom-made ones from lists of genes sent by customers; we then design the oligonucleotides and offer oligo sets based on our catalog arrays."

ONTO THE CHIP

Three basic techniques in common use couple the DNA samples to a chip. In addition to the Affymetrix method of photolithography, which several other vendors use under license, these are mechanical spotting and inkjet deposition. Mechanical spotting involves direct contact with the substrates, which can damage the surface. But until recently it has been able to spot more accurately than noncontact inkjets.

In mechanical spotting, a robotic liquid handling system picks up samples of DNA and deposits them onto the surface of a slide at predetermined locations. The pins used in this system, which can be split quills or solid rods, first come into contact with the DNA sample. Then they apply the sample to the slide by making contact with the slide surface. Washing the pins between applications ensures that any particular DNA sample is not cross-contaminated with another. Suppliers of robotic systems for microarray spotting include BioRobotics Ltd., Cartesian Technologies, GeneMachines, MiraiBio (Hitachi Genetic Systems), and Packard BioScience. This type of spotting system is very popular in academic laboratories owing to its ease of use, low cost, and versatility.

Cartesian Technologies, recently acquired by Genomic Solutions, sells a range of systems for spotting microarrays. "We offer a number of systems ranging from the small benchtop MicroSys, an 11-slide machine for entry level microarraying, up to the PixSys for 50 slides and the 100-slide ProSys," says Don Rose, Cartesian's vice president of research and development. "We're coming out with a new machine, the MegaSys, that will handle about 250 slides and will include a vision system for quality control and automated plate handling." Both systems can be configured with mechanical pins or inkjets.

Inkjet technology was adapted from the personal computer printer industry. A DNA sample is loaded into a tiny nozzle equipped with a piezoelectric device. The device expels a precise amount of DNA from the nozzle onto the slide surface. The nozzle is washed after each deposition to provide a clean nozzle ready for the next sample.

Agilent uses inkjet printing technology developed by its corporate parent, Hewlett-Packard, to manufacture its DNA microarrays. "One thing I find most intriguing about inkjets is the precise volume you can dispense," says Amorese. "It has a profound effect on arrays that every drop fired from the head is essentially the same volume." Agilent uses inkjet heads in two array methods. "For in situ arrays we synthesize oligos in place, using heads that have a continuous feed," Amorese says. "We can also deposit a presynthesized material from inkjets whose heads are filled with very small amounts of material." Other companies that provide inkjet technology include BioRobotics and Packard BioScience.

LABELING, SCANNING, AND HANDLING DATA

Labeling for DNA microarray analysis generally involves fluorescence. Not only does this approach avoid the issues of safety and disposal associated with radioactive markers; it also permits researchers to multiplex samples, permitting them to read several experimental parameters simultaneously. "Fluorescent cyanine dyes are generally preferred for microarray labeling," says Burzcak of Amersham Biosciences. "Other fluorescent technologies are available, but they have a weakness in either linking to nucleic acids or the control of crystal size."

In multiplexing, each probe is labeled with a different fluor that can be simultaneously detected at different wavelengths with optical filters. An RNA sample is converted to labeled cDNA by reverse transcriptase PCR in the presence of fluorescently labeled nucleotide precursors. Genomic DNA is fluorescently labeled by nick translation or random primer techniques. To enable the direct comparison of two samples, scientists label them with different fluors, and then mix them together and hybridize them with a microarray. Agilent, Genpak and Roche Molecular Biochemicals, among other firms, also offer kits for labeling nucleic acid samples.

After hybridization, DNA chips are scanned using instruments specifically designed to detect fluorescent signals. Most manufacturers of imaging instruments use the same principle. A scanning fluorescence microscope illuminates each DNA feature or spot and measures the fluorescence of each fluor or dye separately. Scientists then use these measurements to determine the ratio or relative abundance of the sequence of each specific gene in the two mRNA or DNA samples.

"Right now there are two basic technologies for scanning," says Axon's Pickett. "One uses laser excitation and photomultiplier tube detection. The other uses a white-white system with filters for excitation and a CCD array for image collection." Axon's 4000 B laser scanner is a two-color system. "Its primary benefit is that it is a high performance instrument that is integrated with our GenePix software," says Pickett. "Our customers find it to be easy to use."

QIAGEN's new ultrasensitive SensiChip Reader uses cutting edge planar waveguide technology for microarray analysis. "By coupling the laser light through a diffractive grating onto the waveguiding film of our SensiChip microarrays, we can create an evanescent field whose excitation capacity for fluorescent dyes is limited to 300-400 nanometers," says Potgeter. "The CCD camera detects only the layer with the capture probes and their specific fluorescent targets. This dramatically improves the signal-to-background ratio." Other companies with expertise in such imaging detection include Agilent, GSI Lumonics, Genomic Solutions, and Molecular Dynamics.

Making sense of the large amounts of data collected from gene sequencing and gene expression experiments is no simple task. Scientists who need to manage and analyze the results from DNA microarray work spend many hours working with computers and specialized software to store and manage sequence data, design microarray formats, and analyze the data gathered from their studies. They can obtain help, though, via software solutions developed by BioDiscovery, GeneData AG, LION Bioscience AG, Scanalytics, Silicon Genetics, and Spotfire, among other vendors.

Public databases allow researchers to share the results of their work through the Internet. Researchers can query the large number now available to seek similarities and other relationships between different sets of data. One useful and accurate source of such databases is www.gene-chips.com. This website, maintained by Leming Shi of BASF Corporation, lists databases from the GATC, the National Center for Biotechnology Information (NCBI), the Stanford MicroArray Database, and others. It is also an excellent reference tool for any individual interested in working with microarrays.

FROM GENE EXPRESSION TO SNPS

Understanding how cells function and respond to changes in their environment has intrigued scientists for centuries. DNA microarrays permit researchers to examine cell differentiation, cellular aging, programmed cell death, and various disease processes in greater depth than was possible prior to its emergence in the laboratory. "We use DNA microarrays to understand the changes of gene expression in cells as a function of some drug candidates that my laboratory is working on," says Duke's Pirrung.

Pharmaceutical companies embraced the use of DNA microarrays when they first became available because of their potential for improving the drug discovery process. Their scientists wanted to identify the genes involved in disease processes and to monitor responses to drug candidates. DNA microarrays offered them a new high throughput method for simultaneously evaluating large numbers of genes and monitoring physiological responses to potential drugs. Specifically, DNA microarrays can help researchers to find new drug targets — the molecules with which specific drugs interact — by identifying those genes whose expression levels are altered in a diseased state.

A more recent application for DNA chips occurs in the study of the natural DNA variations among individuals called single nucleotide polymorphisms (SNPs). A SNP is characterized by a single DNA base pair substitution at a specific location in a gene. For example, some individuals in a population may have the base "A" while others may have the base "C" at the same location. Taken together, many of these SNPs can be examined in an individual to develop a type of genetic fingerprint. Scientists can quickly examine the differences using a DNA microarray designed specifically for SNP analysis. This work has value because SNPs can provide information on an individual's predisposition to a given disease. They can even predict how a patient will respond to a particular class of drugs.

STRATEGY FOR SNPS

PolyGenyx, Inc., has developed a unique strategy for SNP analysis. Current technology fixes many thousands of SNPs to a single surface, with each at a separate, defined position on the microarray. This approach has a significant disadvantage: A separate microarray or chip must be used to genotype every single individual. "One of the problems in doing a genome-wide SNP study is how large these studies get relatively quickly," says John Landers, chief scientific officer of PolyGenyx. Thus, a 5,000-individual study would involve 5,000 SNP chips, costing nearly $5 million, for the hybridization detection step alone.

Rather than fixing the SNPs, PolyGenyx's proprietary OmniScan method fixes the genomes of multiple individuals to microarrays. "Through a single PCR reaction we can amplify a random reproducible set of the whole genome," Landers explains. Thus, the SNP detection step now involves hybridizing SNPs, rather than genomes, to the solid surface. This enables genomic DNA from over 10,000 individuals to be arrayed onto a single surface and genotyped simultaneously. This parallel processing approach is substantially more efficient than serial processing for larger population studies.

PolyGenyx is also developing proprietary technologies to enable simultaneous hybridization of multiple SNPs to a single microarrayed surface that will improve efficiency even further. In Landers's view, the method has potential uses in DNA fingerprinting. It could handle the huge backlog at the FBI and other crime labs," he says. "We've also had people ask us about the method's use in foods. It could answer such questions as 'Where does your caviar really come from?' and 'Do your coffee beans come from Colombia?'"

Dionne of Millennium sums up the promise of DNA microarrays and chips. "We think that the real future of microarrays will involve utilizing data better," he says. "That's clearly in the type of experiments done and the analysis and associating not only gene expression but also pathway expression types of data. That's where a lot of our focus is going to be."

Peter Gwynne is a freelance science writer based on Cape Cod, Massachusetts, U.S.A. Gary Heebner is a marketing consultant serving the scientific industry, based in Foristell, Missouri, U.S.A.

WEBLINKS
ADVERTISERS

Agilent Technologies
A leading provider of instrument systems for identification, quantification, analysis, and testing of the molecular, physical, and biological properties of substances and products.
650-752-5000
www.agilent.com/chem/labchip

American Society for Biochemistry and Molecular Biology
The society's purpose is to advance the science of biochemistry and molecular biology through publication of scientific and educational journals, scientific meetings, and advocacy for funding of basic research and education.
301-530-7145
www.asbmb.org

American Type Culture Collection
Diverse materials (such as microorganisms, cell lines, and recombinant DNA materials) to media and other reagents as well as bioscience laboratory services. 703-365-2700
www.atcc.org

Ciphergen Biosystems, Inc.
Develops, manufactures, sells, and services ProteinChip® Systems and related products that discover, characterize, and assay proteins from native biological samples.
510-505-2100
www.ciphergen.com

GeneMachines, Inc.
Provides state-of-the-art solutions for the automation and instrumentation needs of the genomics community.
650-508-1634
www.genemachines.com

Idaho Technology
Makes a broad line of thermocyclers, including the R.A.P.I.D., RapidCycler and Indy thermocyclers.
801-736-6354
www.idahotech.com

Lab Products, Inc.
Designers and manufacturers of the highest quality laboratory animal housing and care equipment.
302-628-4300
www.labproductsinc.com

LION Bioscience, AG [Germany]
Provides information technology (IT) products and integrated software solutions to the life sciences.
+49 6221 4038 0
www.lionbioscience.com

LION Bioscience [USA]

Nanogen, Inc.
Integrates advanced microelectronics and molecular biology into a platform technology with potential commercial applications in the fields of diagnostics, research, genomics, genetics, and drug discovery.
858-410-4897
www.nanogen.com

Packard Biochip Technologies
(PerkinElmer Life Sciences) Manufactures and markets instruments and related consumables and services for use in drug discovery and other life sciences research.
203-639-2598
www.packardbioscience.com

Sequenom, Inc.
A discovery genetics company with the tools, information, and strategies for determining the medical impact of genes and genetic variations.
858-202-9000
www.sequenom.com

FEATURED COMPANIES
and ORGANIZATIONS

Affymetrix, Inc.
DNA microarrays
www.affymetrix.com

Agilent Technologies, Inc.
DNA microarrays
http://www.agilent.com

Amersham Biosciences AB
genomics instruments and reagents
http://www.apbiotech.com

Axon Instruments, Inc.
scanners and software
http://www.axon.com

Azign Bioscience A/S
(formerly Display Systems Biotech)
cDNA microarrays
http://www.azign.com

BASF Corporation
chemicals and fine chemicals
http://www.basf.com

BD Biosciences
sample collection
http://www.bd.com

BioDiscovery
software solutions
http://www.biodiscovery.com

BioRobotics, Ltd.
robotics
http://www.biorobotics.co.uk

Brinkmann - Eppendorf
DNA isolation and purification
http://www.brinkmann.com

Cartesian Technologies, Inc.
robotics
http://www.cartesiantech.com

CLONTECH Laboratories
cDNA microarrays
http://www.clontech.com

Corning, Inc.
laboratory glassware
http://www.corning.com

Duke University
organizations
http://www.duke.edu

GeneData AG
software solutions
http://www.genedata.com

GeneMachines
spotters
http://www.genemachines.com

Genetic Analysis Technology Consortium (GATC)
organizations
http://www.gatconsortium.org

Genetix Group PLC
slides
http://www.genetix.co.uk

Genomic Solutions
(see Cartesian Technologies)
http://www.genomicsolutions.com

Genpak, Ltd.
(Genetix Ltd.) | slides
http://www.genpakdna.com

GSI Lumonics
scanners and software
http://www.gsilumonics.com

Hewlett-Packard
inkjet printing technologies
http://www.hp.com

Invitrogen Corporation
DNA amplification
http://www.invitrogen.com

LION Bioscience, AG
software solutions
http://www.lionbioscience.com

Mergen Ltd.
DNA microarrays
http://www.mergen.com

Millennium Pharmaceuticals, Inc.
pharmaceuticals
http://www.mlnm.com

Millipore Corporation
DNA isolation and purification
http://www.millipore.com

MiraiBio Inc.
(Hitachi Genetic Systems) robotics
http://www.miraibio.com

Molecular Dynamics
(Amersham Pharmacia Biotech) scanners and software
http://www.mdyn.com

MWG Biotech AG
custom DNA microarrays
http://www.mwgdna.com

National Center for
Biotechnology Information

(NCBI) organizations
http://www.ncbi.nlm.nih.gov

Operon Technologies - A Qiagen Company
DNA microarrays
http://www.operon.com

Packard BioScience
robotics
http://www.packardbioscience.com

PolyGenyx, Inc.
SNP analysis
http://www.polygenyx.com

Promega Corporation
DNA isolation and purification
http://www.promega.com

Qiagen GmbH
DNA purification
http://www.qiagen.com

Roche Molecular Biochemicals
DNA labeling kits and reagents
http://www.biochem.roche.com

Scanalytics
software solutions
http://www.scanalytics.com

Schleicher & Schuell, Inc.
slides
http://www.s-and-s.com

Sigma-Genosys
custom oligonucleotides
http://www.sigma-aldrich.com

Silicon Genetics
software solutions
http://www.sigenetics.com

Spotfire, Inc.
software solutions
http://www.spotfire.com

Stanford MicroArray Database
organizations
http://genome-www5.stanford.edu/ MicroArray/SMD

Stanford University
organizations
http://www.stanford.edu

Stratagene
DNA amplification
http://www.stratagene.com

The Institute for Genomic Research (TIGR)
bioinformatic services
http://www.tigr.org

Note: Readers can find out more about the companies and organizations listed by accessing their sites on the World Wide Web (WWW). If the listed organization does not have a site on the WWW or if it is under construction, we have substituted its main telephone number. Every effort has been made to ensure the accuracy of this information. The companies and organizations in this article were selected at random. Their inclusion in this article does not indicate endorsement by either AAAS or Science nor is it meant to imply that their products or services are superior to those of other companies.
This article was published
as a special advertising supplement
in the 4 January issue of Science