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Less is Really More, Research Scientists Say in New York Bioarray Conference


What do scientists want from a microarray platform?

Less, said participants at last week’s inaugural BioArrays 2003 conference in New York City.

“The future of diagnostic prognostication involves a small number of genes — a small number, but one where quality counts,” said conference attendee Steve Gullans, chief science officer of Woburn, Mass.-based US Genomics and an associate professor at Harvard Medical School, and Brigham and Women’s Hospital, in Boston.

These sentiments emerged just as microarray giants Affymetrix and Agilent Technologies battled by press release on Oct. 2 to claim the lead in the race to commercialize microarrays that have the known coding content of the human genome on a single chip (see below).

But at the two-day conference, which was sponsored by GeneExpression Systems, a four-year-old genomics contract research company established by former PerkinElmer scientist Krishnarao Appasani, the message was clear: researchers are using microarray analysis to conduct thousands of assays, in order to create short lists of genes on which to base further research, and to simplify the task of analyzing the gigabytes of data that such wide efforts produce.

“Even 200 genes is a lot to think about,” said Jose Walewski, an assistant professor at New York’s Mt. Sinai School of Medicine who is conducting research on liver disease, concentrating on using microarray analysis to find pathways involving the hepatitis C virus and liver cancer.

“Microarrays have enormous value, but there is a real need to know the truth,” said Thomas Vasicek of Lynx Therapeutics. Vasicek, a Harvard Medical School PhD in genetics and immunology, has cycled through thousands of microarrays in a career that saw him manage Millennium Pharmaceuticals’ microarray technologies — followed by a stint as director of commercial technology for Corning’s short-lived effort in microarray manufacturing — and a position as a visiting scientist at the Whitehead Institute, where he evaluated genomic technologies.

There is no doubt that microarrays have provided a previously unavailable insight into genomic functions and systems. But it is a technology that is still lacking the highest measures of accuracy and confidence that are to needed in the future — where it is seen as a key element to enabling the dream of personalized medicine.

Before the tool enters this personalized medicine arena, scientists said they want issues with hybridization-based assays solved.

“P53 chips miss mutations,” said Francis Barany, a professor of molecular biology at Cornell’s Weill Medical College in New York. “The commercial hybridization chips miss more than 25 percent of all mutations. If patients’ lives depend on it, the chips need to be accurate.”

Sam Hanash, a professor of pediatrics at the University of Michigan and the first president of the Human Proteome Organization, presented the following wish list for diagnostic tests:

“For the diagnostic tool set, you need to get samples in a non-invasive manner — blood, urine, or saliva, are easy to get; simple sample preparation; simple instrumentation; easily interpretable data; low cost; and, in the real world, something that is 100 percent accurate.”

Hanash is a flag-bearer for the knowledge that proteomics will bring, as well as the orders of magnitude in complexity that accompany this logical next step in the exploration of systems biology.

“You are much closer to a clinical outcome with proteins, rather than a hundred genes,” he said. “but no single technology allows a researcher to study all aspects of proteins at once. “

Protein microarrays offer promise, but lack capture agents, he said, offering an optimistic prediction: “It’s just a matter of time before we have those resources.”

For David Munroe, director of the lab of molecular technology, and vice president of program management at the National Cancer Institute, Frederick, one promising technology is Nanogen’s electronic microarray platform. NCI has an early-access relationship with San Diego-based Nanogen and is perhaps one of the company’s key users.

“We have used it (Nanogen) for the admission of patients into clinical trials,” he said. “It allows for exquisite determination between alleles. The only limitation with the platform is that it is not high throughput. But, it is simple to operate and we love it for diagnostics.”

Other companies are targeting the space too.

US Genomics, which started up with the goal of enabling human genomes to be sequenced for $1,000 or less using its flow cytometry platform, is now looking to RNA analysis and is hoping to begin commercializing its instrument before the end of the year, said Gullans in a presentation entitled “Looking for a few Good Genes.”

For the microarray industry, the opportunity is there to provide the answers that scientists are seeking next. Its advantage right now is that there are few substitute technologies available that can enable the numerous experiments that can be conducted using microarrays.

“Microarrays are the main tool, but certainly not the only one,” said Jeffrey Waring, group leader for toxicogenomics for cellular and molecular toxicology at Abbott Laboratories. “Taqman assays would be quite good if we could get the list [of genes being studied] smaller.”

Meeting Notes

While all of the above are critical issues in the development path of the microarray technology, there are other issues at play too — intellectual property rights and funding.

The conference ended with a panel discussion on these topics by an academic technology transfer officer, a venture capitalist, and two lawyers specializing in intellectual property practice.

Joseph Lawler, an MD/PhD and a principal with the New York venture capital firm of JP Morgan Partners, did not paint a promising picture for those hopeful of earning early-stage funding for genomic platform technologies.

“Many investors are not as excited about platform technologies,” he said. Entrepreneurs in this space would have to show that a platform is unique and can speed a drug’s progress to the clinic, according to Lawler. Microarrays, which enable researchers to look at thousands of genes, might cast too wide a net for characterizations that can be based on 10 genes and can be done with another technology, Lawler said.

Entrepreneurs seeking funding should have a credible business plan, he said, and should know that the first decision-points an investor will analyze are the management team and the science involved. “If the science is bad, even the best management team won’t help,” he said

But while the hope of venture-capital funding might be dim, there are other funding vehicles available.

Kenneth Sonnenfeld, an attorney with the New York firm of Morgan & Finnegan, suggested partnerships for microarray content inventors. “Get it tested and get it out there, marketed on someone else’s array,” he said.

Sam Hanash, also participating on the panel, suggested taking financing through the public domain.

“Submitting a proposal to the NIH is an option,” he said. “There are plenty of avenues with the NIH to get funding.”

For many researchers in the audience, the principal question appeared to be about the viability of patenting genes.

Duncan Greenhalgh, an attorney and a PhD practicing with the Boston-based law firm of Testa, Hurwitz & Thibeault, said that patents can be granted for “new uses for old compositions of matter.” Inventors, he added, are obliged to disclose to patent exam-iners all prior art they are aware exists in patent applications.



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