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Illumina Hopes to Sow the Beads Of a Second Microarray Revolution

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Inside the mirrored glass walls of its expansive La Jolla, Calif., headquarters, Illumina is trying to make the microarray revolution happen all over again.

The company’s technological manifesto centers around a platform not visible to the naked eye — a fiber optic stalk that holds at its tip a sunflower seed pod of 50,000 microbeads, each in its own semispherical well and labeled with a fluorescent tag. There are 25 of each kind of labeled bead, making for 2,000 unique beads per bundle.

These bundles can be placed on 96-, 384-, or even 1,536-well plates, yielding a dizzying array of arrays. A 1,536-well plate holds more than 3 million uniquely labeled beads and a standard 96-well plate has 192,000 assays.

“The density is so far beyond all other arrays,” said Jay Flatley, the company’s CEO, during an exclusive interview with BioArray News at the company’s headquarters last week. “We have the ability to put 10 times more content on our real estate.”

While these days many genomics companies are abandoning such pure-play tools talk in favor of target discovery business plans, Illumina is holding to its high-tech California dream. The company believes in its technology so much that it is shooting for the post-genomics triple crown — genotyping, expression, and proteomics — in commercializing its bead arrays.

 

Genotyping Network

 

Of the three-pronged application strategy for Illumina’s technology, genotyping seems to be the strongest so far. Illumina has signed seven genotyping agreements, including a recent one with GlaxoSmithKline, and a new one with Oxagen, a British clinical genomics company.

As a genotyping technology, Illumina’s bead arrays are competing against large, sequential machines like Sequenom’s MassArray, similar to the way network computing competed with mainframes. This gives Illumina a potential advantage: if one cog in its wheel of arrays and machines that control them needs to be scaled up, that piece can be taken out and improved. In the other systems, the whole machine would be shut down or replaced. Also, while Sequenom can do hundreds of thousands of genotypes per day with its new 31.5 square meter MassArray 200k, Illumina — at least theoretically — can do far more with far less. The company says it has done half a million genotypes in a day so far, but could easily do a million, all on one well plate. (Sequenom has also said it can scale up to a million genotypes per day.)

One way Illumina speeds up the process is in multiplexing 384 PCR reactions, a process that the company says it is likely planning to keep for itself.

The company has also partnered with Applied Biosystems to offer its arrays as a commercial product for genotyping, tentatively entitled Lite Brite. ABI is developing the scanner for this system, along with assays from its project to resequence the genomes of 50 people for genetic variation.

The system will be able to analyze 100,000 genotypes per plate, and several plates will be able to run in a single day, according to a presentation by John West, ABI’s vice president of DNA platform business management, at the Tri-Genome conference last month.

Illumina is also developing its own “Sherlock” scanner outside the ABI partnership.

 

Waiting for a Market

 

These products offer promise, but there is one problem: Their market doesn’t quite exist yet. Currently, there is only a handful of SNPs reliably correlated with disease. While there is a small short-term market in genotyping discovery work, Illumina is banking on the likelihood that in a couple of years, the blocks of SNPs that make up most human genetic variation will be mapped out and reliably associated with disease or drug response. Then, Illumina believes there will be a rich vein of demand from pharmaceutical companies to genotype patient samples.

“In a few years, every person in a clinical trial will be genotyped,” said Flatley. Illumina believes its platform, which can profile 2,000 SNPs of 96 or 384 patients at a time, will be ideal for this purpose.

The problem is, scientists say that while haplotype maps will be completed in as little as two years, the association of haplotypes with disease could take a decade.

“The limiting factor in finding genes that cause disease — once the obstacles of genotyping technology and the current unavailability of a haplotype map are overcome — will be obtaining appropriate human sample collections and using them in these studies,” said David Reich of the Whitehead Institute.

So what does Illumina do in the mean time? The Nasdaq-traded company had $94 million in the bank as of December 2001, down from $118 million the previous year-end, which means it burned $24 million in cash last year. At this burn rate, the company will run out of fuel some time near the end of 2005 — which could be well before pharmaceutical companies start haplotyping everyone they study. Even if Illumina’s early products are used for SNP discovery, there is still a big gap to fill.

 

Oligator Dance

 

To cover its short-term revenue needs, Illumina has developed an oligonucleotide business with its Oligator farm. The farm, a series of machines each named for a Sesame Street character, churns out oligonucleotides 760 at a time, with a 95 percent success rate, according to Flatley. “Our intent is to become a very serious player in the oligo business,” he said.

The company is offering its oligos at 18 cents per base, but has acknowledged that its turnaround time is not as fast as some of its competitors. Flatley said the company is now working on a five-day turnaround time.

Meanwhile, Illumina is adapting its arrays for gene expression and proteomics. For expression, the company has developed its ZipExpress technology. The company also says it has done “a couple of studies on proteomics,” demonstrating the feasibility of its sandwich assays. But in this arena, the magic fiber optic bundles do not excuse Illumina from the challenges that plague other proteomics array companies, such as the instability of proteins and the lack of content. is looking to partner with other companies to provide content.

— MMJ