One of the hottest buzzwords in biotechnology in 2004 was “systems biology.” And although the phrase means different things to different people, the overarching theme is one of surveying the activity of an entire biological system at once, rather than bits and pieces of it as has been the trend over the past few decades.
In many ways, systems biology is a step away from viewing the -omics technologies that sprung forth from the sequencing of the human genome as separate entities. Instead, scientists are now beginning to re-examine how genomics and proteomics fit into the context of the bigger picture — the cell — and nowhere has this trend been more apparent than in the field of drug discovery.
Pharmaceutical scientists have long conducted drug screening assays on living cells, but they have typically come in two flavors: cell-based assays that yield one or a few data points, much like their biochemical counterparts; or microscopy-based assays that produce richer content, but are painstakingly slow.
Pittsburgh, Penn.-based Cellomics showed several years ago that there may be a better way with the invention of “high-content” cellular screening, and it implemented a strategy to make the technique as widely available as possible. In the past year, that strategy may have finally paid off, as the biotechnology industry saw a boom in instrument platforms for cellular analysis, as well as myriad acquisitions and licensing agreements that served to stake a claim for larger, publicly traded biotechnology companies.
“In 2004, [high-content screening] reached enough critical mass to make the world realize that it is a future trend and not just a passing fad,” said Judy Masucci, director of marketing at Cellomics. “Now that every single one of the top 20 pharmaceutical companies, as well as numerous biotech and academic research centers, have started to utilize HCS technologies and invest in HCS, this market is getting noticed.”
Drug discovery outfits are looking for new ways to determine the full scope of a drug’s activity earlier in the screening process — not surprising in the wake of a relatively negative year for the industry. Despite any progress made by pharma in 2004, the year will likely be remembered most for the toxicity concerns and eventual market withdrawal of the popular pain medication Vioxx, as well as subsequent concerns about similar COX-2 inhibitors.
Of course, these are extreme examples of toxicity effects that slipped through the cracks, and it may be a stretch to say that high-content screening and cell-based assays could have prevented it. But the number of otherwise efficacious drugs that ultimately fail at later stages due to toxicity is still huge. Consequently, pharmaceutical companies are looking for new methods to help them fail faster, as PerkinElmer spokesperson Dan Sutherby told Inside Bioassays earlier this year, and cell-based assays — high-content screening, in particular — top the list of possible solutions.
“[HCS’s] advantages are being seen across all areas in drug discovery,” Masucci said, “from early lead optimization and target identification or validation, to high-throughput screening … and even more importantly into [toxicity], where millions of dollars can be saved in drug development by determining the toxicological profiles of drug candidates before they go into animal studies and human trials.
“By using cell-based assays and high-content screening, this early and more thorough profiling of compounds will ultimately save millions and allow companies to produce drugs that are better analyzed than ever before,” Masucci added.
Biochemical assays and in vivo small-animal models still have a very prominent place in drug discovery, but high-content cell-based assays represent the best of both worlds. They’re not as high-throughput as biochemical assays, but they yield much greater depth of information. On the other hand, high-content cell-based assays provide nearly the same amount of data as live-animal assays, but are faster, more easily controlled, and more convenient overall.
This was not always the case, but the throughput and amount of data generated by cellular analysis technology has increased exponentially in the past few years.
“[One] reason for the interest in high-content screening is that the technology has become mature and robust enough to be useful and for pharma and biotech to see an advantage in that use,” Mark Collins, Cellomics’ senior product manager for informatics, said. “Also, we think that the overall trend, driven in part by systems biology, to do ‘more better’ rather than ‘more faster’ is ideally suited to the … contextual approach of HCS.”
“Cellular analysis fits in nicely with the drug discovery industry’s interest in systems biology,” Michelle Boudreau, director of corporate communications at Caliper Life Sciences, said. “Scientists are looking for ways to better understand as much as possible about the biological system they are targeting.
“One part of this is making sure that the model used for a particular assay is as close to the in vivo conditions as possible, thus the increasing interest in cell-based assays,” Boudreau added. “There is also a hope that cellular assays will continue to reduce the amount of whole-animal testing required for a drug to be launched. Cellular assays are a critical bridge between in vitro biochemical assays and animal models.”
Who Bought What?
A sure sign that a particular field is rapidly growing is an inordinate amount of merger and acquisition activity, and the HCS arena provided a perfect example.
“With all of this attention, companies like GE, Beckman Coulter, and Becton Dickinson started to take notice of this emerging market and saw value in it,” Masucci added. “For that reason, many of the small start-up companies have gotten purchased, as the quickest way to enter a market is to purchase a small company that has products and give it the marketing and sales backbone to grow faster.”
Although Cellomics is widely credited with inventing high-content cellular screening, the real boom probably started late in 2003 when GE announced plans to acquire Amersham Biosciences. Amersham manufactured the IN Cell Analyzer cellular analysis instrument, perhaps the only real competitor at that time to Cellomics’ ArrayScan and KineticScan cellular analysis platforms.
Soon thereafter, the floodgates opened — perennial rivals Beckman Coulter and Becton Dickinson made their moves, as BC first snatched up San Diego-based Q3DM and its flagship high-throughput microscopy system, and BD later made a splash with the acquisition of Rockville, Md.-based Atto Bioscience and its confocal-like spinning disc cellular analysis platform. Both companies quickly repackaged their new platforms and put them on the market before the year was through.
In the meantime, Cellomics was anything but an idle bystander. In fact, it was arguably the busiest of its counterparts. Among many other initiatives, Cellomics launched a new cellular analysis and storage software package; signed a deal with IBM to store and manage HCS data; licensed core HCS patents to GE Healthcare and BD Biosciences; and pushed into China by forging a deal with that country’s National Drug Screening Center.
Other publicly traded companies involved in the cell-based assay boom included Caliper, PerkinElmer, and Molecular Devices.
Of these, only Molecular Devices has a true high-content cellular analysis system in its Discovery-1 platform. But the company also has several systems for conducting ion channel screening, kinetic assays, and end-point assays on living cells, and it bolstered all of its cell-based assay tools — or at least eliminated a major competitor — with a March acquisition of Axon.
Although Caliper and PerkinElmer have yet to launch high-content platforms per se, each has made significant strides in shoring up its cell-based assay platforms. Caliper’s major move was a May acquisition of cell culture techniques, hardware, and software from Amphora that increased the ability to assay primary cells on Caliper’s LabChip microfluidics platform.
PerkinElmer, meanwhile, extended the ability of its customers to conduct ion channel, GPCR, and protein-protein interaction screens by forging agreements with Australian biotech Bionomics and Danish biotech BioImage.
Rounding out the high-content screening market are Evotec’s confocal-based Opera system; TTP Labtech’s Acumen Explorer; CompuCyte’s iCyte and iCys high-content cell-based imaging cytometers; and Amnis’ ImageStream 100 flow-based imaging system. Evotec has garnered its share of customers, but has not made any significant upgrades to its existing system, and TTP Labtech has been one of the few relatively quiet HCS players. CompuCyte and Amnis just launched their instruments within the last few months, and early returns on their potential profitability are inconclusive.
Lastly, key cellular assay reagent technologies further infiltrated the market, such as BioImage’s Redistribution assays for monitoring protein-protein interactions in live cells, and North Carolina-based Norak Biosciences’ Transfluor fluorescence relocation assays for screening against a broad range of GPCRs. Each of these companies had a busy year in which they secured new IP, and licensed their assay technologies out to scores of toolmakers and pharma companies.