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Gene Expression Microarray Technology Advance Gets NSF Grant

Genes hold the answers to cancer.

To help detect and study genetic changes in cells more quickly and efficiently, NJIT's Timothy Chang, PhD, associate professor of electrical and computer engineering, was recently awarded a three-year, $640,000 National Science Foundation grant. Chang, working with Patricia Soteropoulos, PhD, Director of the Public Health Research Institute's Center for Applied Genomics, has developed a robotic technique for getting genetic material onto slides precisely, quickly, and cheaply.

The grant will cover the cost of research and developing a prototype system, he says. Eventually, the new process will make gene-based diagnosis of cancer and other diseases so much faster and cheaper that even small hospitals across the nation will be able to perform it, Chang says. Currently hospitals send samples of genetic material to major centers for analysis, at a cost that can reach $5,000 per slide. If Chang is successful, hospitals will be able to purchase affordable equipment  and then do all the testing they want.

Chang, who with his colleagues holds several patents on the new process, has come up with a new system for placing minute dots of material into a "microarray"--a grid on a slide.  The key features of this microarray system include using  a "smart pin." The pin uses a fiber-optic pin and a pressure-sensitive sensor/actuator known as a piezoelectric nanopositioning device to get  precisely the right amount of DNA material, protein or other sample on the slide.

The concept is to replace the current hollow steel  pin used to squirt samples of genetic material onto a slide with the "smart pin" guided by electronic sensors. That should eliminate a major drawback of hollow-pin technology, says Chang. The hollow pin splashes the material onto the slide, much as a dot-matrix printer puts ink on paper. It also makes contact with the glass, ultimately  wearing down the pin and damaging the glass.

The smart pin can move in three directions and the sensor gives the user feedback to be certain the spots of matter placed on the slide are exactly the right size and density.  It also maintains a uniform gap distance between the pin tip and the target slide to make the  process consistent and reliable. Chang says this new technology, known as a fully automated microarray fabrication system, has the potential to speed up cancer research and treatment, as well as identifying other agents of disease. 

 "Current technology utilizes only about 20 percent of the sample on the slide. The rest is wasted." Chang says his Smart pin technology --which uses an optical fiber to deliver the genetic material to the slide--will thus greatly increase the amount of testing that can be done with a sample.

Mutations in genes within a human cell can mean that the cell has turned cancerous, or that an inherited trait associated with developing genetic disease or cancer is present, or that the disease has progressed to the stage where it is getting ready to spread.  The process of examining cancer cells starts with taking a sample of the patient's tissue and putting it on a slide. The tissue may be tumor material, blood, bone, skin, or from an organ. Decades ago, researchers could only look at that cellular material's shape and/or growth pattern to make a diagnosis. But with genetic research, they are now starting to see deep inside the cell's inner workings, down to DNA, the molecules that make up the genes. Known formally as deoxyribonucleic acid, DNA holds the information that carries  the operating instructions for normal cellular operations including growth and cellular death. Defects in just one letter in the DNA can lead to the out-of-control cellular growth and refusal to die that is cancer.

To examine cells at such a fine level, the cellular material may first be processed to extract either DNA or the proteins DNA produces, or the molecules that make up those proteins, or that make up DNA.  Once isolated, amplified, and labeled with a fluorescent dye, the genetic material must then be applied to a grid-patterned microarray on a slide containing the target genetic materials (commonly cDNA or oligonucleotides). This process is called hybridization where the matching DNA oligonucleotides will bond with the corresponding targets on the microarray while the non-matching materials will be washed off. This way, the genetic material can be identified by checking for proper fluorescence properties. Each spot of the microarray has to be the same size. And with the process of isolating the genetic material an expensive one, no one wants to waste it, as current technologies tend to do.

Using a laboratory technique called gene expression profiling, scientists are now often able to spot these abnormal genes so quickly that the technology has the potential to revolutionize the diagnosis and ultimately the treatment of many kinds of cancer. In effect, researchers can now make a molecular profile of a cancerous cell. They can then save that profile and make it available to other scientists through the Internet. Cancer research is not  the only use for the lab technique.  According to Chang, the same approach--making a genetic profile of an infectious agent can enable rapid identification during an outbreak.

If DNA is the blueprint of life, then proteins are the building blocks of every living thing. The next step in the genetic revolution is proteiomics and the smart pin technology can be readily applied to produce protein chips which will be central to understanding life at a molecular level.

Chang says that because of the NJIT research, the technology to do such genetic analysis may soon be within the reach of  far more institutions. Currently such research activities are concentrated in major centers. That's because the process of getting a sample of genetic material onto a slide and analyzing it costs between $1,200 and $5,000 per slide. Since 70 percent of that expense is having an outside company prepare the slide, NJIT/PHRI are developing this low-cost, high performance and fully automated system so that small research institutions and laboratories could buy the system then prepare their own slides, quickly, precisely and cheaply.

One of the key features of the new technology is in its high precision. Right now, laboratory tests indicate Chang's device is capable of positioning spots at a positioning resolution of  two  nanometers-- a minute distance equal to one two-hundredth the wavelength of light, or the width of the DNA double helix.  “We are improving the precision of the smart pin so it can eventually work directly on the nucleotides one day”, says Chang.

For the DNA microarray, the system deposits a droplet of genetic material as small as 0.05 nanoliter on a microscope glass slide. Because the system will be extremely exacting, it will be able to increase the number of droplets on the slide to 150,000 spots from the current limit of 40,000 spots. "That means we could fit the entire human gene sequence on once slide," he says.

The system also has a "software layer," in the form of a  Universal Web Interface that connects the platform to the Internet with real-time data streaming. The new system will also make it possible for far more researchers to share their research findings through the Internet., with a goal of getting better diagnosis and treatment to patients more quickly."

"You could be anywhere in the world, have the right password, and have access to the machines and  database," Chang says. That would enable researchers to match their own samples to genetically analyzed examples of cells.  Leukemia researchers have recently used gene expression profiling to distinguish between subtypes of the disease. That is important because the subtypes have different prognoses and treatments.

There are many diseases and conditions that might benefit from gene research. For instance, scientists here  have already used the technology to look at what happens to rats' nerve cells after a spinal cord injury. In some cases the damage had been repaired. By identifying which genes are associated with this regeneration they have opened the possibility that there may be a way to stimulate these cells to grow.

Currently the Center for Applied Genomics' Microarray Core Facility has ongoing  research projects with 51 collaborators and 14 service users in 24 different institutions across the nation.

NJIT also has an industry partner on board. Genemachines, Inc., one of the leading manufacturers of microarrayers, is donating an Omnigrid microarrayer and engineering time to the project. The company is also helping NJIT make the new technology available commercially.  Chang says the research is part of a wave of technology developments that have scientists saying that genomic research is seeing an "industrial revolution."

"We love small things," he says.---Gale Scott