18 Apr Madison biochip research offers geneticists a big view through a small window
Some biochips barely cover a human thumbnail, but they can hold over a half of a million samples of DNA.
And because this emerging technology offers a view of so many tiny bits of information at once, it’s perfect for studying relationships among the 30,000 genes of the human genome, which are one of biology’s next major mysteries.
Biochips, essentially slides with many tiny dots of sample material on them, give scientists a chance to look at bits of DNA side-by-side. These genetic patterns may appear normal or abnormal; and depending on where the abnormality is, they may reveal links in a “pathway” that correlates with tumor production, for example.
“There’s been a big shift over the past five years or so away from individual genes or small functions toward complex systems, complex pathways,” said Stan Rose, CEO of NimbleGen Systems.
Headquartered in Madison, NimbleGen links with University of Wisconsin to use and advance research in biochips. It uses a technology developed at the university, micro-mirrors, to cut chip production times down from months to days.
Biochips as they function today represent a 10-year-old wave of experimentation and application. Most of the first five years of biochip research involved DNA analysis, in sync with scientists’ preoccupation with the gene-mapping project.
The oldest applications of biochips for DNA analysis are still used and involve a technique known as spotted array. Ink jets or porous pin heads spray up to 10,000 samples of DNA – produced meticulously in tiny test tubes – onto a slide or chip. Researchers design masks that block or allow light in specific areas on the chip and place the masks over the samples before exposing the chip to light, after which some DNA strands will continue to grow and some will stop.
Samples that remained in the darkness will latch onto more base pairs and form different strand lengths on the surface of the chip. These different segment lengths help scientists determine patterns among the strands. After researchers prepare the spotted array, they analyze legible pictures of it using computers.
The masks can take months to develop, and the test-tube samples require much work to prepare and store. For this reason, researchers worked with photo-chemistry to eliminates masks and test-tube samples and generally surpass microarray techniques. They even increased the sample size 80 times.
“If you use photo-lithography, our way, the spots are smaller and you can get 800,000 on a surface the sized of a cover slip,” Rose said.
DNA biochips have a secure place in the market – they’re estimated as a $1 billion industry – and many researchers prefer to work with them. Other researchers, like Robert Negm of GenTel Biosurfaces, wanted to get into something they feel is in a take-off stage, like protein biochips.
Predicted to jump from $200,000 industry to a $500,000 industry by 2008, protein biochips are based on more complex, less predictable chemical processes.
They offer more chances to approach diseases themselves, before it’s too late to treat them. Protein analysis can also improve how we treat a disease that out-responds standard therapy, Negm said. Proteins are the products of genes, and the logical next step in tracking and controlling disease.
“Proteins are really the molecules in biology that deliver on function and structure, they are more important in targeting disease,” said Negm, who recently joined the research team at GenTel to work with protein biochips. GenTel Biosurfaces is another Madison-based company that incorporates research from the university.
“DNA micro-arrays can tell you if you express a gene or not. But this does not tell how those genes are expressed in the body and how they produce proteins, and those proteins are the culprits,” said Alex Vodenlich, CEO of GenTel.
For now, protein biochips remain in the shadows of established DNA research. The reason is simple: DNA has four base pairs that combine in a predictable and controllable way. Proteins, on the other hand, involve 20 amino acids and form an estimated 5 million shapes and sizes. Yet they cause action and reaction and create structure, and that’s why they’re attracting people like Negm and Vodenlich.
Researchers who choose to study proteins realize the bottleneck of initially slow experimentation – you can only fit up to 1000 samples on a protein chip these days – and they experience glitches in how amino acids behave and fit together. Still, they say, the push beyond these setbacks will be worth it.
In the end, researchers say they value smaller biochip-size samples that are consistent and clear. They want the best view of microprocesses, faster.
“We’re in this new field of science to look at all these genes at once and look at patterns,” Rose said.