In the drug discovery industry, cellular assays have undoubtedly taken a turn towards image-based analysis — and tool makers have followed suit, unleashing a bevy of microscopy-based cell-based screening systems over the past year.
But not all tool makers have adopted the same approach. One example is San Diego-based Acea Biosciences, whose flagship cellular assay technology is based on microelectronics.
The privately owned company, which was started in mid-2002, has secured a first round of financing, CEO James O’Connell told Inside Bioassays last week, although it has kept the details of that fund-raising under wraps.
Now Acea is attempting to scare up additional funds in a series B, which O’Connell believes the company can complete by the second quarter of this year.
Acea launched its flagship platform, the RT-CES (Real-Time Cell Electronic Sensing) system, in mid-2004. Since that time, the company has been hitting trade shows pretty hard, and, according to O’Connell, has placed about 50 systems — “about 30 of which are at big pharmaceutical companies,” he said.
At approximately $65,000 a pop, that figures to be a little over $3 million in revenues generated in the past year, not counting assay consumables, which Acea also sells along with the RT-CES.
The full platform comprises an electronic sensing chip; a so-called device station; an analyzer; and associated software. The technology is patent-pending in Europe and the US, according to the company.
“Basically the technology is based on an electronic sensor,” Xiaobo Wang, Acea’s chief technology officer and vice-president of R&D, told Inside Bioassays last week. “We take a 96-well plate, and inside each well of that plate, we incorporate a microelectronic sensor. We actually use a so-called bottomless microtiter plate, and we have the sensors on glass slides, and then we assemble the glass slides to the bottom of the plate.”
According to Wang, the electronic sensing slides are placed inside an incubator, and are connected to a microelectronic processor of sorts known as the device station. This in turn is hooked up externally to a computer-controlled analyzer.
Under software control, the analyzer can perform electronic measurements on the individual sensors continuously — “maybe every five minutes, or every couple of hours; basically, whatever time interval you set,” Wang said.
“The signal that we’re measuring is electronic impedance of the sensors,” Wang explained. “This impedance relates to a couple of physical characteristics or parameters of cellular status, such as the number of cells present, morphology of the cells, and the degree of cell adhesion. For instance, if there are more cells present, the impedance would be higher, or if they’re spread out more, the impedance will also be different.”
The obvious advantage of Acea’s technology over other cellular analysis platforms on the market is that it is label-free. Adherent cells — and they must be adherent in order to contact the microelectronics — are grown or spotted in the well plates as is. This translates to cellular behavior that is presumably more “natural” than if bulky molecular labels such as GFP are attached to or expressed inside a cell.
Secondly, the assays are truly kinetic, and monitor cellular activity continuously over long periods of time, during which the cells can be challenged with various small molecules.
But is the system, which measures only a few “physical” characteristics of the cells, robust enough to be useful in higher-end drug discovery applications? On the surface, it would appear not, but Acea is banking on the fact that it can convince users that these tiny physical characteristic changes can constitute a “signature” of sorts for certain types of cells, or the same type of cell being challenged by a variety of externally applied biomolecules.
“A good example would be in cancer cells, looking at a compound that causes apoptosis,” Wang said. “Depending on what kind of molecule you use, and depending on what kind of molecular targets were in the cells, the impedance changes over time are different. Let’s say this compound is interacting with microtubules and causing some inhibition of mitosis — then you see a kinetic response. Or if the compound is basically a cell-cycle blocker, then you would see another type of kinetic response.”
Wang said the same concept can be applied to a number of other important assays in drug discovery, such as GPCR-ligand interactions and kinase activity, each of which Acea believes cause the cell to undergo significant enough physical changes to provide a unique signature via the microelectronic sensors.
Of course, each of these signatures must be determined in a number of control experiments prior to any type of screening, so researchers have a reference point.
“In the beginning, you would want to make certain all the conditions are right,” Wang said. “But on the other hand, with the proper control, the signal can become very, very specific. If you take two cell lines, with one expressing a specific receptor … when you apply the ligand, you can see an obvious dose-dependency, and you see that the temporal response is different.”
And the exact nature of the cellular change may not be determinable from the impedance changes, which is why the platform seems to lean more towards high-throughput cell assay potential, rather than high-content cellular analysis. Consequently, the platform may not be appropriate for so-called primary or secondary screening applications, but more for “back-end research work,” according to Wang.
“I don’t think at this moment anyone is using our system for primary or secondary screening,” he said. “But they are using it for things like assay development, target validation, and compound optimization. This is all because the throughput is not high enough.”
Already, though, plans are in the works for Acea to increase the platform’s throughput, by gradually increasing the well-plate density from 96 wells to higher figures such as 384 and 1,536, based on “a number of customer requests,” Wang said.
Once the throughput is increased, “we would probably move towards secondary screening first,” Wang said. “There is really no technical limitation to developing those devices [or] for developing that software, but it will take some time to get there.”
Additionally, although Acea has no formal partnerships in place, Wang and O’Connell both noted that there may be some synergy with other types of screening platforms, such as those based on microscopy or fluorescence and luminescence detection.
“We clearly do see potential,” O’Connell said. “There may be some creative ways to employ our technology along with an imaging system, for example, and we’ve had some early discussions with those kinds of companies.
“For a small company, focus is everything, so we’re trying to stay focused on what we’re doing to get these systems placed, and get our manufacturing under control — those kinds of things,” he added. “But I think there are a lot of advantages to maybe at some point integrating this technology with others, for a slightly different application. Of course, we’re always looking for those kinds of things.”