Protein Power
Zina Moukheiber, Forbes Magazine, 11.12.01
Proteins are hot, as upstarts race to create new tools to study them. Zyomyx may be first.
Large Scale Biology is a small company with big dreams in the hottest new field in medical research: proteomics. At its lab in Germantown, Md. it takes 20 hours for machines to separate out and study a single protein from a blood sample containing 20,000 of them. Once a protein is marked with blue dye, a photocopier-size machine sequences and identifies it. The lab can handle only 1,000 samples in a week.
Lawrence Cohen wants to solve the lab's problem by replacing the machines with a new biochip the size of a Pentium.It will identify and analyze thousands of proteins in a couple of hours. His firm, Zyomyx, is at the front of a pack of shops racing to create the new biochips as the premier tool for decoding the role of proteins in disease. In a few years Zyomyx and rivals such as HTS Biosystems and SomaLogic hope to be selling thousands of chips to drug researchers.
"The reality behind the hype of pinpointing new drug targets will not come to fruition without bringing efficiency to protein analysis," says Cohen, chief executive of Hayward, Calif.-based Zyomyx, privately held and funded with $65 million in venture money.
Researchers completed the map of the human genome a year ago, identifying all of the 30,000 genes that define a human being. Now comes an even tougher task: They must decipher the 1 million or so proteins that are produced at the instructions of those genes. Proteins, not genes, are the targets of most drug development, and only 2,000 or so are known.
Protein chips will be used by drug companies to find promising new compounds and to screen patients for trials. Labs will use them in diagnostics, much like a quick pregnancy test. A handsome market beckons: close to half a billion dollars in sales in five years, by some estimates. A related technology, DNA chips for analyzing genes, now has sales of $400 million a year and could hit $1 billion by 2006.
But creating protein-sifting chips will be far more difficult. DNA is comparatively simple to analyze--it consists of only four chemical units in varying mixes. Proteins are made up of various patterns of 20 amino acids, and they take on contorted 3-D shapes. The way they fold determines their function. Current technology requires "drying up" a protein to study it, removing it from its natural setting, which can distort a strand's form and function.
Zyomyx's founder, Peter Wagner, a 38-year-old German-born biophysicist, has studied how to improve protein analysis for the past decade. In the early 1990s he was looking at ways to tether proteins to solid surfaces, a must to study single proteins and how they function. He decided to shroud proteins in the protective coating of a salt-water-like solution of organic molecules, similar to the body fluids that ordinarily envelop proteins. He also concocted special surface chemistries to pin them down.
Wagner saw the success of DNA chipmaker Affymetrix and dreamed of following the same path with protein chips. He founded Zyomyx in 1998 with Stanford biochemist Steffen Nock. In search of funding, he gave 200 talks to drug researchers and investors, many of whom were skeptical. The race to map the human genome "was at its peak," he says, "and people were thinking DNA, not proteins." In 1998 he landed $1 million in seed money from Skyline Venture Partners.
Zyomyx's chips, which it hopes to have in tests at six biotech boutiques and research labs by mid-2002, use layers of antibodies as Velcro-like hooks to capture and quickly identify protein content in a blood or tissue sample.
Wagner started on his first protein processor, a 10mm-by-10mm slip of silicon, by etching into it 1,500 pillars, each 50 microns in diameter--enough room to hold 100,000 proteins of a single type. The chip, divided into groups of 250 pillars in six isolated chambers, allows researchers to compare six different blood samples. Current techniques analyze only one sample at a time.
In a test to prove the chip can match a blood sample's proteins against an existing set of known antibodies, Wagner and Nock chose a hot list of 25 tiny proteins called cytokines. They are the messenger molecules of the immune system, relaying information to the body's army of killer T cells and B cells.
In the test, a robotic arm descended onto the chip, carrying a slate of 1,500 microscopic reservoirs holding antibodies known to bind to cytokines. The arm plopped the antibodies down onto the tips of the 1,500 pillars. Through tiny ports, a needle injected 10 microliters of bloodonto the chip surface. Half an hour later the deposited antibodies had latched on to the cytokines in the blood sample, and the blood was washed off. A second set of cytokine-specific antibodies was layered on top, sandwiching the target proteins. These upper antibodies were tagged with fluorescent dye to detect binding. Sure enough, all 25 of the cytokines were tagged and identified, proving the chip did its job. Zyomyx hopes to have the new chips in full production by 2003.
Specialty Laboratories, a Santa Monica, Calif.-based testing firm, is evaluating the use of Zyomyx's cytokine chip to diagnose diseases. Protein markers can provide clues to whether a case of hardened arteries is caused by inflammation or a cholesterol disorder.
Canadian testing company MDS has teamed with Zyomyx to develop a chip that can detect protein interactions inside cells. To test it MDS used two proteins known to play a key role in cancer:ras and GRF2.
Researchers placed the ras protein on the chip, then took GRF2, tagged it with a fluorescent dye and mixed it with a million other proteins from a serum sample. After washing off the liquid, a colored dot confirmed that the ras protein had bound to GRF2, showing their link in a couple of hours--a relationship that had taken scientists years to find out. MDS' ultimate goal is to develop a potent cancer drug.
Advances in proteomics will spur a new era of highly targeted drugs--and enrich those who create the best tools. "We're developing the first Gutenberg for proteins," Wagner says. |
