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Wake Forest Lab-On-Bead Technology May Be 10K Times Faster Than Current Cell Assays

This article has been updated from a previous version to clarify the name of the technology in the headline and to correct the amount of sample and reagent required for PCR. 
A group of investigators led by scientists at Wake Forest University has developed a drug-screening method using fluorescent nanoscopic beads that they claim can be as much as 10,000 times faster than currently used methods that expose only small numbers of candidate compounds to cultured cells at any one time.
As part of $527,000 in funding from various agencies, including the American Cancer Society, the project received $235,000 in funding from the North Carolina Biotechnology Center and a $227,000 phase 1 grant from the National Cancer Institute, a Wake Forest University official told CBA News.      
In addition, the researchers have applied for, but have not yet received, a $2.25 million grant from the NCI.
The technique is based on functionalizing nanoscopic beads with drug molecules. Among them are aptamer molecules that have the potential to bind other target molecules.     
Guthold declined to elaborate on the process used to functionalize the beads.
The beads range in size from about 50 nm to about 1 micrometer, depending on the screening.
“We have this vast library of beads that are functionalized with aptamer molecules. Each bead has a different DNA sequence, a different potential drug candidate on it,” Guthold said.
“We would take this vast library of different beads and we would flow it over the cancer cells that over-express the Her2 marker,” said Guthold. From underneath, the binding events between the aptamer-containing beads and the cancer cells can be observed.
“The tricky task then becomes pulling out the beads [that have bound to the cancer cells] and identifying them.”
The researchers actually have two methods to accomplish this. On top of the cells, there is an atomic-force microscope with a small tip that they can use to spear the beads that are bound to the cells and then “pull them out of the sample,” Guthold said.
“We would then scrape it off into a microfluidic device, and PCR amplify it to identify the aptamer molecule that was on the bead,” he explained.
Beads that bind to a cancer cell can also be retrieved with a tiny micropipette. “You can apply suction to that and potentially can pull up a bead, so that we could retrieve it out of the pool and inject it into a microfluidic chamber, and again, PCR amplify it and identify it,” said Guthold.

“The tricky task then becomes pulling out the beads [that have bound to the cancer cells] and identifying them.”

Guthold did mention one caveat, however: “We actually have not applied it to cells yet, but we have the cells in hand, and we want to go ahead and use it.”
Guthold said that one of his team’s collaborators, Dongqing Li’s group at the University of Waterloo in Ontario, is developing a device to automate the lab-on-a-bead process and facilitate parallel processing to speed up screening campaigns.  
“We can use the individual microbeads, and we can also do the on-chip PCR, so we can dramatically reduce the cost of screening,” Li told CBA News this week. In conventional drug discovery, large volumes of reagents are needed. The technology works on a micro- and nanoscale, so it reduces sample and reagent cost.
“And we are using individual microbeads, so we can have an array of tests conducted in a very short time using a very small amount of sample and reagent,” Li said.
For instance, when using conventional devices to do PCR, scientists need perhaps 50 µL of sample and reagent. Using Li’s chips, they would need between 1 µL and 5 µL, he said. “So the cost is dramatically reduced as well, and it is much faster,” said Li.
He added that this technology could also eventually be used to screen actual chemical compounds in the beads, rather than aptamers.
The beads are basically a central processing unit: They carry the molecules, they are used as a visualization aid, they are fluorescent so they can be seen, and they are being used as a handle because the scientists use the bead to retrieve the aptamer molecule.
“So the functionalized little bead is actually a key player in this technology,” said Guthold.
In the future, “We want to find molecules that bind to molecules on cancer cells, such as Her2. You can use the purified protein itself, or you can select from whole cells, which will be a little trickier, but we do want to go that way,” said Guthold.
He also said his team would like to integrate their microscopes with microfluidics, and that is where Li, a microfluidics expert, comes into play.
“Eventually, we want to develop lab-on-a-chip devices so that the entire process can automatically be done on a chip,” Li said.
A NJ-based start-up company, NanoMedica, which will soon open an office in Winston-Salem, NC, has expressed an interest in commercializing this technology, Guthold said.

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