SAN FRANCISCO — Although cellular imaging was the topic du jour at Cambridge Healthtech Institute’s High-Content Analysis conference here last week, not everyone was necessarily on the same page.
Executives from Royston, UK-based TTP Labtech were in attendance, and although the company didn’t exhibit at the conference, it did present a pair of posters describing the capabilities of its Acumen Explorer microplate scanning cytometer — a non-image-based platform for which the company is still trying to carve an appropriate niche in drug screening.
The Acumen Explorer falls somewhere in between a microscope and a flow cytometer in its capabilities. TTP Labtech’s challenge has been, and continues to be, positioning the instrument’s unique capabilities within the drug-screening process.
“Cellular imaging, which we’ve heard a lot about at this conference — we don’t offer that very high resolution,” Wayne Bowen, TTP Labtech’s chief scientific officer told Inside Bioassays last week. “But in a screening mode, you don’t often need that.
“But we can still do some of the basic assays and get the answer very quickly,” Bowen added. “We’re trying to propose an integrated approach where we can tell the scientist very quickly that something has occurred in that well. And that’s often the aim of the high-throughput screening campaign.”
The Acumen is suitable for a range of basic cell-based assays such as apoptosis, proliferation, cytotoxicity, cell cycle, mitotic index, kinases, and protein translocation. Wylie said that the company has in particular focused on kinases and cell cycle analysis.
Unlike most plate-based high-content screening systems, the Acumen Explorer does not use a CCD camera to collect confocal or other fluorescent images. Instead, it trains a 488-nm laser on individual cells, quickly scanning from one well to the next, and collects emission data with photomultiplier tubes via appropriate filter sets — up to four separate channels.
The strength of this approach, as TTP sees it, is that it can perform high-content analysis much faster than can systems that generate terabytes of image-based data, possibly making the Acumen Explorer more appropriate for a primary high-throughput screen — an area in which image-based systems have yet to find success.
However, the major feature that the Acumen shares with high-content imaging systems is that it is meant to be used with live cells. Thus, the Acumen is somewhat of a “‘tweener,” since high-throughput screening is still very much the realm of biochemical assays.
“For people [who] have got an imaging system, we can make if more efficient for them,” said TTP Labtech scientist Paul Wylie. “But we have to do it on our system first. We can use the power of other [HCS] systems to really focus in on [their] interesting compounds after the main screen.”
Wylie related his point to a panel discussion at the HCA meeting as part of the compound-screening track of the conference. The chairperson of this particular track asked a panel of pharmaceutical scientists whether drug discovery has reached the point where one can use cell-based screening from start to finish, or whether a biochemical assay must always be a part of the process. All three panelists agreed that biochemical assays are still necessary.
But Wylie and Bowen might be among the first to disagree. They believe the Acumen has the potential to be the first high-content cell-based system to also have a high-enough throughput for primary screening.
Of course, the phrase “high content” is still a bit subjective, and manufacturers of imaging systems — such as Cellomics, GE Healthcare, Evotec, BD Biosciences, Beckman Coulter, and Molecular Devices — have clearly made an effort to make the terms “high content” and “imaging” synonymous.
“One thing that we’re trying to drive is that there’s a big difference between high-content analysis and high-content screening,” Bowen concluded. “When people fundamentally understand that, then they will see where the Acumen Explorer fits.”
Regardless of Bowen’s argument, the field has clearly shifted towards the imaging-as-HCS paradigm, and TTP has thus had to re-evaluate the competitive marketplace.
“I think when the Acumen first came out, we positioned ourselves against imaging systems, which is a crazy thing to do, because we are quite different,” Wylie said. “We are faster, but we haven’t got the resolution and information that they have. So now, we’re positioned in such a way that no one is really competing against us, because no one does what we do.”
TTP Labtech must now convince potential customers of its philosophy. It is unclear exactly how much revenue the company has already generated from instrument sales, but it claims to have a roster of clients spanning pharma and biotech. But many of those instruments were in place prior to this past year, when the imaging boom really began.
Wylie and Bowen noted that the company is comfortable with projected future sales; regardless, TTP has recently initiated a series of moves it anticipates will generate additional revenue.
Perhaps most notable is the company’s announcement last week that it has partnered with Harlow, UK-based drug-discovery firm Argenta Discovery to offer custom assay development and screening services — TTP Labtech’s first foray into such an area.
“We’ve obviously got the experience — we’re in the lab developing new assays to show capability on the Explorer, and we’ve been doing this now for four years,” Wylie said. “So if somebody wants an assay done, we would develop it at TTP Labtech, and then pass it on to Argenta, who’ve got one of our machines, and then they would run the screen, because they’re actually a screening company with a lot of experience in dealing with compounds, et cetera.”
Wylie and Bowen also said that TTP Labtech is focusing heavily on the complementarity the instrument might have with two assay technologies, one old and one new: ß-lactamase reporter gene assays and quantum dots. Both of these technologies have been made more compatible with the recent addition of a 405-nm laser to the Acumen Explorer.
“What we’re seeing now for the ß-lactamase is that the move into a high-content readout on a cell-by-cell basis is having marked benefits over bulk fluorescence,” Bowen said. “We’re able to use a hundred-fold fewer cells in each well, and the screening windows are sometimes 10-fold higher than a bulk read. So when you’re thinking about high-throughput screening, which is really where ß-lactamase assays reside, those two factors alone can have significant cost benefits.”
Wylie added that the ß-lactamase assay is starting to regain popularity in drug screening because it is no longer under license from Invitrogen, which had charged “huge licensing fees” for the technology. Instead of licensing the technology from Invitrogen, scientists need only obtain the appropriate reagents now.
A potential collaboration with Hayward, Calif.-based Quantum Dot also makes sense, although there is no official partnership in place. The most attractive feature of Quantum Dot’s semiconductor nanocrystal probes is their distinct emission spectra, which make for easier multiplexing. Because the four filters can be changed quickly on the Acumen Explorer, the instrument can be much more quickly adapted to imaging multiple tags than can other image-based platforms, Wylie said.
Last year, Wylie told Inside Bioassays that a basic 488-nm Acumen, with 2 PMTs and a slower read-card, costs about £104,000 (about $186,000); while a top model with all 4 channels of fluorescence and a faster read time costs about £154,000 ($276,000). Some may view the price as slightly high for a system that doesn’t capture images. The lasers are what ultimately drive the price up, but it is also what gives the Acumen its high throughput — about three minutes on average for a GPCR assay on a standard well plate; four minutes for a kinase assay; and 13 minutes for a cell cycle assay, according to the company’s website.
“We’ve tried to create this area called microplate cytometry, and we don’t have the intermediate step of having the image,” Bowen said. “We use the laser to actually find the object — that’s why it’s cytometry — it’s exactly like a flow is working.
“In terms of cost, the Acumen and HCS readers are fundamentally different machines,” he added. “We are more in the price range of flow cytometers, where the market being driven down and down.”
Even if the Acumen can’t find a permanent home in the drug screening process, TTP Labtech has the cushion of being a division of the profitable UK-based company, TTP (The Technology Partnership), which offers a combination of products and consultancy services in a variety of tech-based industries.
Bowen and Wylie said that TTP was founded with some initial seed funding, and since then, the company’s consultancy wing has driven its growth. TTP also has a policy of incubating companies internally rather than seeking external VC funding. “It’s been a very successful strategy for us,” Bowen said. “It can limit maybe the speed at which we can develop, but it’s also a very safe model for us.”
The Labtech branch also has additional capabilities, such as in bacterial detection and automated chemistry, and “even 50 percent of Labtech’s revenues come from consultancy,” Bowen added.