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By Salvatore Salamone

September 9, 2002 | Two different nanotechnology proof-of-concept tests have demonstrated that microarrays can in theory be shrunk significantly so probes on the arrays are much higher in density. But before placing orders for these new nanoarrays, a fundamental stumbling block needs to be overcome -- can relevant biological data be extracted from such devices?

Earlier this summer, researchers at Northwestern University teamed with nanotechnology company NanoInk Inc. to demonstrate that a technique called dip-pen nanolithography could be used to produce ultra-high-density gene chips. The technique produces spots of DNA on a gene chip as small as 50 nanometers (billionths of a meter) in diameter. By contrast, today’s gene chips use spots that are about 20 to 40 micrometers (millionths of a meter).

“With this new tool, we can miniaturize a normal chip that’s made and sold today for studying a problem in genomics,” said Chad Mirkin, Northwestern professor and co-founder of NanoInk, in a statement released by the university to announce the results of this test that were published in the journal Science in June.

Mirkin notes that today’s microarrays have 100,000 different spots, each about 50 microns in diameter. “Using dip-pen nanolithography, we can we can prepare 100,000 spots in the area occupied by a single spot in a conventional array,” says Mirkin.

Also this summer, BioForce Nanosciences Inc., which bills itself as a developer of nanoarray biomolecular analysis systems, was awarded a $500,000 small business innovative research grant from the National Institutes of Health. The award is to fund the building and validation of a tool for creating nanoarrays, which BioForce Nanosciences calls the Nanoarrayer.

These nanoarrays could be used to study protein interactions and for drug discovery research. According to the company, the Nanoarrayer will create arrays by placing thousands of molecules at specific locations with great accuracy. BioForce Nanosciences says this means a single spot on a nanoarray will have as many probes as there are today on an entire microarray.

Both the Northwestern University and BioForce Nanosciences projects are considered very leading edge with no definite timetable from moving from proof-of-concept to commercialization and widespread use.

Before that happens, the question of how small a probe can be and still yield relevant biological information has to be answered. If this technology were taken to its limit, a successful event on the array would be one gene or molecule interacting with one probe.

“This is cool technology, but is it good science?” asks Steve Bodovitz, technology navigator at the biotechnology and pharmaceutical strategy consulting company BioInsights. He notes that such one molecule, single interaction events are interesting, but asks “how low [in the number of probes] can you go and still get relevant biological information out?”

The unanswered question is how much useful information can be collected from microarrays. Systems that read the information look at either an optical or electrical signal coming from the microarray. If only a relatively small number of biological events occur in a single location on an array, the resulting small signal could go undetected.

Compounding the potential problem is that all electrical and optical systems produce background noise. A weak signal can be very hard to detect amid background noise, but help is on the way. “The issue with microarrays today is how do you detect a weak signal,” says Douglas Lane, Vialogy CEO and president. The problem is only going to be magnified with nanoarrays.

“Today tens of millions of [the same] probe are placed on one spot of a microarray chip,” says Lane. “And tens of thousands or millions of strands of DNA stick to the probes. If one molecule sticks, you might not be able to detect it.”

Vialogy has developed signal processing techniques based on quantum resonance interferometry that helps extract information that might otherwise go undetected from microarrays, protein arrays and other biochips. Vialogy claims its techniques will enable instruments to detect the signal from biological and chemical events up to 10,000 times lower than background noise level.

Currently, Vialogy has several patents on its quantum resonance interferometry signal processing technologies and is moving to develop an enterprise version of its technology for drug discovery.


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