On a cold Chicago day in the late 1990s, physicist David Grier was fiddling around in his laboratory with a cheap piece of plastic and a laser. Grier and a graduate student named Eric Dufresne were trying to build a new kind of “optical trap” — a device that splits a laser beam and uses it to capture particles of a single substance. Multiple traps, used in tandem, could let the scientists play traffic cop on a molecular level, separating a substance into component parts — removing bacteria from blood, for example. But first they had to make it work. For a year, Grier and Dufresne had been trying out fancy glass splitters, but nothing had done the trick. On this day (to help protect his patent, Grier won’t say exactly when it was), they tried a $5 piece of plastic as a joke. “It should not have worked,” Grier says. Yet it did — where earlier optical traps could capture a maximum of two substances, this cheap plastic one split the laser beam into 16 parts which, when properly harnessed, gave them the potential to trap 16 separate substances. It was the breakthrough they had been after for years. “We were stunned,” Grier recalls.
Soon after that jaw-dropping development, Grier co-founded Arryx. With a product called BioRyx, Arryx has now perfected the laser-beam splitting technique into what it calls a set of “optical tweezers.” But we prefer the traffic-cop analogy: picture a busy time-lapse video of crisscrossing highways, bridges and underpasses, and you get an idea of what matter looks like in a BioRyx under a microscope. BioRyx picks up different substances and tells them where to go. The technology today is used for everything from analyzing blood to separating the sperm cells in bull semen that produce bulls from those that make cows (which might not seem important unless you’re a dairy farmer who needs a supply of milk- and cheese-producing females).
Arryx is one of 29 Technology Pioneers chosen this year by the World Economic Forum, the nonprofit organization of global political and business leaders best known for its annual meeting in Davos, Switzerland. Selected from among 114 nominees by a panel of technology experts, the Pioneers’ biotech developments augur advances that will help people live longer, healthier, more productive lives. Pioneers like Arryx; Astex, a biotech firm in Cambridge, England; Raven Biotechnologies and Xencor, both in California; and Memory Pharmaceuticals of Montvale, New Jersey, are targeting cancer, Alzheimer’s, nutrition, animal husbandry — you name it. Their innovations are a testimony to the do-it-yourself spirit that fuels both technology and entrepreneurship. Indeed, many of this year’s Pioneers had to leave comfortable corporate or academic jobs in order to solve problems that have confounded others for years. “You could hear the people at Caltech snicker,” says Xencor co-founder Bassil Dahiyat, recalling his graduate days at California Institute of Technology when he proposed that since protein shapes vary according to their functions, one could create new disease-fighting proteins by first imagining their shape. Looks like he may be right — Dahiyat now says
He is a year away from marketing protein-based drugs to treat arthritis and multiple sclerosis. For the luckier Pioneers like Grier and Dufresne, the distance between the initial “Eureka!” moment and a marketable business can be breathtakingly brief. It’s true that they were not the first to develop an optical trap. This has been a hot area of scientific inquiry at least since 1986, when Bell Labs invented one. (Grier had done a postdoctoral fellowship at Bell Labs.) Back then, Bell Labs scientists invented a single-beam “optical tweezers” that trapped just one substance. That was a monumental breakthrough, but scientists began to ponder traps that could catch multiple substances and move them from one point to another. Since their plastic fantastic moment gave Grier and Dufresne 16 separate optical traps, that was enough for the University of Chicago to eventually showcase the duo to Lewis Gruber, a biotech entrepreneur and patent lawyer. Within months, he had invested in the technology, and Arryx was born, with Gruber as chief executive. Grier today is its chief scientific adviser, and a professor at New York University.Gruber, Grier and company have long since replaced the plastic with a liquid-crystal device, which they build into a small, box-shaped machine that you could call a cell catcher. Arryx has dubbed it CellRyx. Where BioRyx is useful “for anyone with a need to have hands in the microscopic world,” notes Grier, CellRyx is specifically for sorting cells. A blood-equipment company, Gruber says, will soon purchase a CellRyx that will remove platelets from donated blood. The platelets, which induce clotting, would then be given to hemophiliacs. The same blood machine could remove bacterial cells, or could extract red cells to give to anemics. The CellRyx box operates faster and captures much smaller particles than the centrifuges and filters that medical laboratories use today, says Gruber.
Harren Jhoti, too, made a discovery that had eluded better-funded corporate researchers. In October 2002, Jhoti and his colleagues at Astex discovered in their Cambridge lab a chemical that bound to a protein called beta-secretase (Bace), which researchers had identified as a possible cause of Alzheimer’s disease. The chemical was just a fragment of what could eventually become an Alzheimer’s-conquering drug. But it represented a big step in the quest for a Bace-targeting substance, which drug giant AstraZeneca had been seeking for years; the firm enlisted Astex’s help. “AstraZeneca worked on it for four years. We delivered an early drug candidate within a year of signing with them,” says Jhoti, who is Astex’s founder and chief scientist.
How did they do it? By deploying a process called X-ray crystallography. First, they grew a Bace crystal. Then they exposed it to an array of X-rays. A protein is too small to be “seen” by a normal X-ray, but if run through a series of rays, it will produce a recognizable pattern of small dots — it’s a bit like seeing the bear in the pattern of stars that make up Ursa Major. The crystallography technique was once used by legendary dna discoverers James Watson and Francis Crick. As Jhoti notes, “it took Watson and Crick over a decade just to image one dna molecule.” Astex has sped up the process with a series of computer algorithms and hardware processes.
Astex calls its drug discovery method “fragment-based,” because rather than throwing an entire proposed drug molecule at the target protein, they throw just pieces at a time. Jhoti claims this yields a much higher success rate than trying out whole molecules, an approach favored by large drug companies like the one he left in 1999, Glaxo Wellcome (now GSK).
Astex has also developed a general anticancer chemical that Jhoti says has the potential to stop all cancers at a very early stage by thwarting the initial cell-division process. He hopes to win regulatory approval to begin testing the drug on humans in the first half of 2005.
A different approach to Alzheimer’s is being pursued at Memory Pharmaceuticals. Drawing on Nobel-prizewinning research by co-founder Eric Kandel, the company hopes to develop drugs that reverse dementia, memory loss, depression and schizophrenia. Chief executive Tony Scullion says it has already developed a drug that fights Alzheimer’s by restoring the process by which short-term memories are logged in for long-term recall. Swiss drug firm Roche is now testing it on humans, with clinical results expected in the near future.
Another disease-fighting Pioneer is Jennie Mather of Raven Biotechnologies in South San Francisco. Like Jhoti, Mather is out to fight cancer, but her approach is radically different. She postulated that what really counts in a target protein — that is, a protein that causes a disease and that a drug would aim to disable — is the protein’s surface. Since a body’s natural antibodies never enter a diseased cell but do their work entirely on the cell’s exterior, she reasoned, drugs should work the same way. Such thinking was heresy to her former employer Genentech, which analyzes a target’s entire genetic structure. “They were just interested in genomics,” she says. “There are 500 to 1,000 genes in a disease — the problem is, it takes a long time to understand what 1,000 genes do.” Genomic drug development can typically take four to five years. Mather figures she can cut times down to an average of about six to nine months.
But to test her theory in a lab dish, she needed to get around the problem that human cells die outside the body. She created a patent-pending process to keep them alive, and her efforts paid off. Mather hopes that the Food and Drug Administration in the U.S. will soon approve one of her drugs for human testing. The drug, called raag 12, is a protein that in the dish destroys another protein found in 90% of all gastrointestinal cancers and in 50% of of all breast, lung and prostate cancers. It works by crippling the cancer cell’s surface, she says.
A few hundred miles south at Xencor in Monrovia, California, Dahiyat is also experimenting with proteins that he hopes will become disease-fighting drugs. If all goes as planned at his Caltech spin-off, in about a year Xencor will start human trials of a protein that combats multiple sclerosis, rheumatoid arthritis and other diseases.
His drug targets a protein called Tumor Necrosis Factor (TNK). TNK can help immune systems fight infections and tumors, but an excess of it causes inflammatory diseases. Xencor’s protein binds with the excess TNK and shuts it down. The company believes this is a superior approach to existing treatments, which simply seek to lower TNK levels. Xencor’s approach derives from a process Dahiyat invented in 1997 while a graduate student at Caltech. Instead of using time-consuming methods like trial and error, he asked a computer to figure out what mix of amino acids would make a protein of a particular shape. (Shape is important because a protein’s structure determines its function. Just like a flathead screwdriver is appropriate for some jobs and a Philips for others, proteins’ different shapes help them effectively attack different disease cells.) The desired shape is easy to figure out; finding the single protein in a world populated by trillions of them is the hard part.
In 1997, Dahiyat wanted to show that he could make a V-shaped protein with a coil falling off the top of one arm. His Caltech colleagues laughed, but off he went to the supercomputer at Caltech’s famed Jet Propulsion Laboratory. “I said, here’s the shape I want to make, tell us the sequence,” he recalls. By the end of the day, the computer gave him billions of possible amino acid combinations and recommended the best one. Dahiyat threw that sequence into a small, tunnel-like device called an NMR spectrometer. About a minute later, Dahiyat noticed that the V-shaped protein was indeed falling into place. “I could see it wasn’t spaghetti. I said, ‘Oh my God, we’ve got structure!’” Thus was born a protein-creation process that Dahiyat calls Protein Design Automation (PDA) and that became the foundation of Xencor. PDA no longer requires supercomputing power but can run on a mere PC. Dahiyat’s team is now applying their techniques to other therapeutic drugs that they hope will boost the human immune system.
Most of the Pioneers are a long way from marketing their drugs. Clinical trials can typically last for four or five years before regulators approve or reject their general use. But if in a few years their efforts are aiding those with crippling diseases like Alzheimer’s and cancer, it will be testament to a well-known scientific theorem: sometimes you’ve gotta quit the day job.