Through the Screen Door
Sitting in the Kalypsys boardroom, dressed all in black despite the summer weather, John McKearn says he used to be a serial killer – of drug candidates. The company’s president and chief scientific officer is talking about the problem he saw during his stint at Pharmacia, the Peapack, NJ, pharmaceutical company acquired by drug giant Pfizer in 2003. According to McKearn, companies test thousands of candidates in series, wasting precious time and money on one compound only to find that it fails in some respect and then moving on to test another. To survive, McKearn says, drug companies must learn to screen compounds in parallel and to kill, or reject, the unpromising ones as early as possible. That’s what Kalypsys aims to do.
The bottom line: McKearn predicts that Kalypsys’s technology can shave 50 percent off the time and cost of traditional drug development. Considering that drug companies average $800 million in R&D investment for each compound that receives FDA approval, that’s no idle boast. McKearn points out that Kalypsys took only six months to discover new anti-inflammatory drug candidates in animals – a process he says would take most drug companies two to three years – and plans to seek the FDA’s permission to test its first drug on people in 2005. But of course, “the proof of the pudding is in the eating,” says Janice Reichert, senior research fellow at the Tufts Center for the Study of Drug Development. “They have a good system, but it’s not revolutionary.”
Not yet, at least. Indeed, translating the latest biology into new small-molecule drugs has universally proven difficult. “Pharma [the pharmaceutical industry] is unprepared for the post-genomic age,” McKearn says. The numbers game is daunting. Consider that the 30,000 genes in the human genome code for the activity of roughly 200,000 proteins. So far, scientists have discovered small molecules that interact in a predictable way with only about 500 proteins.
Kalypsys’s technology could change that. Walking up to a thick door near the company’s main entrance, McKearn touches his index finger to a fingerprint scanner and swipes his identification badge through the door reader. Where McKearn’s face should be, the badge has a picture of Dr. Evil from the Austin Powers films, a nod to McKearn’s “evil plan” to disrupt traditional drug discovery and outcompete large drug companies. Inside the room are three large yellow robot arms standing at attention. Every few seconds, one of the robots springs to life, using a mechanical gripper to lift a small tray of chemicals out of a storage unit and swiveling to stack it at the next testing station.
On this day, the machines are doing tests on blood cells from leukemia patients and proteins suspected to be involved in the disease. One robot gathers 9-by-13-centimeter trays, dispensing samples – some proteins, some whole cells – into 1,536 tiny wells. The samples have been designed or modified to fluoresce when a protein’s activity is altered or there is a physical change in a cell. In another set of trays are small molecules, which a second robot squirts into the samples; it puts the resulting mixtures into an incubator. After the prescribed incubation time, the third robot picks up the test mixtures and places them in an optical chamber, where they are examined by highly sensitive cameras. A central computer coordinates the robots and records the results of the tests.
The system allows the researchers to investigate a wide range of compounds and targets – and kill off dead ends – fast. “We were quite impressed,” says NIH’s Collins. For one thing, only one person needs to be present to start the machine, as opposed to the dozens of workers needed to run most big screening systems. The system operates day and night, screening a million compounds every day, which is more than many large drug companies can do.
After a long day, Simon Tisminezky, Kalypsys’s business development manager, leads a tour of the company’s manufacturing plant, a few kilometers away. This is where Kalypsys is building next-generation screening machines for itself, NIH, and a few other customers; it delivered a similar system to Merck in mid-2004. The facility, a cross between an airplane hangar and an auto mechanic’s garage, is dark and empty after hours. So far, workers have completed incubators and storage units for the NIH system. By winter, Kalypsys plans to have a complete robotic system up and running; engineers will test the whole platform, then take it apart and ship it to NIH piece by piece.
Because its business plan calls for this sort of technology transfer, Kalypsys is building more than a machine: it’s building a gateway between basic research and drug development. It will give a new community of scientists unparalleled access to the world’s most advanced tools for probing the genome. Those tools could eventually change the way science and drug discovery are done. After the tour, Tisminezky is careful to set the security alarm as he leaves the facility and steps out into the setting sun.