That National Heart, Lung, and Blood Institute has awarded Vala Sciences a $249,866 Small Business Innovation Research Grant to develop a live-cell high-content screening assay to detect cardiac myocytes that have differentiated from embryonic stem cells.
The SBIR is the third grant the company has received from the National Institutes of Health since the summer. In July, the National Institute of Diabetes and Digestive and Kidney Diseases awarded Vala $142,606 to develop an assay to study lipid droplet formation in human fat cells. In September, NIDDK followed that with a $200,371 grant for an automated screen for small-molecule modulators of insulin mRNA synthesis.
Patrick McDonough, director of biology at Vala and the principal investigator on all three grants, told Cell-Based Assay News that the NHLBI SBIR grant is “unique” among the company’s other awards in that it will help it develop its first hardware system for high-content screening. As part of the assay it is developing under the grant, the firm is building an electrode assembly that will plug into third-party HCS workstations.
McDonough noted that cardiac myocytes contract in culture just as they do in the heart. The contraction is caused by a transient increase in intracellular calcium concentration, “and we can detect that visually if we load the cells with a fluorescent calcium indicator,” he said. “We’ll put in electrodes to stimulate them, and if we see certain cells light up — literally like a light bulb — we know that calcium has gone up inside them in response to stimulation, which is what a heart cell does.”
Vala is developing the assay in collaboration with Mark Mercola, a researcher at the Burnham Institute who specializes in cardiac regeneration from embryonic stem cells. “The idea is that researchers would want to screen chemical libraries to see what chemicals might enhance the differentiation process to produce more cardiac myocytes from embryonic stem cells,” McDonough said.
The assay could potentially have broader applications, however. In fact, the company initially began developing the system to study toxic effects on mature heart cells, and McDonough said that the final instrument ought to be able to meet that goal.
“The idea was that a lot of chemotherapy agents for cancer are toxic to the heart, so we proposed several times [to the NIH] to develop an instrument that would quantify the effects of these agents on heart cells by looking at their calcium transients,” he said.
After speaking to Mercola, however, “we realized that the same instrumentation could work effectively on … the differentiation of cardiac myocytes from embryonic stem cells,” he said.
McDonough was unable to provide a commercialization timeline for the instrument, noting that it is still very early in the Phase I stage of the grant, which runs through next March. The award has received “fast-track” status from NIH, he said, which means that it should be approved for Phase II funding “without too much trouble.”
Vala is initially developing the electrode and controller assembly to plug into Beckman’s IC100 HCS workstation because it uses that system in house. The goal, however, is to enable the system to work with as many third-party systems as possible.
“From a commercialization standpoint, the goal is to make it easy to interface with whatever’s out there,” he said.
McDonough added that uncertainty around the commercial future of the IC100 [see CBA News 2/17/06] heightens the necessity for vendor neutrality.
Since it was founded in 2004, Vala Sciences’ mission has been to develop reagents and software to support image-based cell assays, and its other two recent grants, which both support software development, are more in line with that strategy.
The lipid droplet assay, which the company is co-developing with cell line provider Zen-Bio, will be able to quantify the amount and size of lipid droplets that form in human fat cells after treatment with small molecules or other chemicals.
McDonough said that the assay “doesn’t require much in the way of sample processing, but it requires imaging, and the analysis of the image by the software is actually the limiting factor in how fast that can occur, so that’s the main thrust of our development and research.”
The “obvious” application for the assay is obesity research, McDonough said, where human cell lines should prove to be a much better model system than the mouse cell lines that are commonly used.
More “subtle” applications include type 2 diabetes research, where studies have shown that existing drugs like rosiglitizone actually cause fat cells to develop more and larger lipid droplets. Although the biological mechanisms behind this phenomenon are still unclear, it could prove an effective shortcut in drug screening, McDonough said. “Pharmaceutical companies interested in finding chemicals that will cure diabetes could test them on fat cells to see if they make them more fat,” he explained.
“We’ll put in electrodes to stimulate them, and if we see certain cells light up — literally like a light bulb — we know that calcium has gone up inside them in response to stimulation, which is what a heart cell does.”
Another potential application area for the lipid assay is HIV drug discovery, where reverse-transcriptase HIV inhibitors have been shown to inhibit fat deposits. “It’s of concern, so pharmaceutical companies might be interested in testing their reverse transcriptase inhibitors in this very same system,” McDonough said.
Vala’s second NIDDK grant — another collaboration with Mercola of the Burnham Institute — is targeted toward type 1 diabetes. McDonough said that the assay uses a cell line that’s been engineered to automatically detect the production of insulin.
“Again, from our standpoint, the data acquisition is easy — that’s all been worked out,” McDonough said. “It’s the analysis side” that requires further development.
McDonough said that the goal of the two software-development projects is to develop plug-ins for Vala’s current image cytometry software package, called Thora. However, he noted that both projects are still in their early stages and didn’t rule out the possibility that Vala may develop standalone software packages for these assays.