Ruth Coxeter

Earlier this century, Lucille Ball and Mae West charmed the crowds here. Now, on the site of the old Audubon Ballroom, some scientific upstarts hope to earn raves, too. Their audience includes everyone from Wall Street to the U.S. Food and Drug Administration. Columbia's Audubon Biomedical Science and Technology Park is home to 15 emerging biotechnology companies. Here, scientists hope to apply biological knowledge for human good; along the way, they hope to please a few shareholders. The discoveries range from artificial skin for burn victims to genes that may one day help us better diagnose and treat cancers. Their origins are diverse, from one couple's mission to help their ill son to a Columbia gene hunter's dream of starting his own company.

Calling the exterminator: VITEX
An antique advertisement for "Vegetine: The Great Blood Purifier" hangs in the sunlit office of VITEX executive vice president Dr. Bernard Horowitz. The ad promises rosy cheeks, a ringworm cure, and relief from a dozen other ailments. Today, Horowitz's startup firm has a tougher mission: ensuring the purity of the nation's blood supply. Despite stringent screening, blood-borne viruses such as HIV and those causing hepatitis B and C sneak through undetected, sometimes through simple human error. Blood safety is at even greater risk in developing countries, which cannot afford the latest screening technology.

What's your risk of contracting these viruses? About one in every 30,000 units transfused, says Horowitz. With the average transfusion at five units, the risk jumps to one in 6,000. Viruses have a window of opportunity because the body does not make enough antibodies to detect them until some time after the initial exposure. Questions about sexual behavior and drug use attempt to filter out risky donors, but a recent report in the Journal of the American Medical Association surveyed 35,000 people and found that one in 50 failed to mention a risk factor when they last gave blood.1 These omissions represent a potential public health problem and a major opportunity for VITEX.

"There's always a new virus, always a test sensitivity limit," says Horowitz. "So to achieve the 100 percent safety which we think the public really demands, we use viral inactivation." That's what V.I. Technologies stands for. VITEX was founded in 1995 as a for-profit spinoff of the New York Blood Center, the country's biggest independent blood distributor. The ability to exterminate viruses, supported by a stable of nearly 30 patents, has allowed VITEX to assemble a wide range of safe blood products in or about to begin clinical trials, ranging from biological glues that could eliminate the need for surgical sutures to fresh frozen plasma for transfusions.

Horowitz compares the company's ability to vanquish viruses to "washing the dirt out of dirty clothes." He and a team of researchers developed a solvent-detergent process that literally soaps away the protective fatty envelope surrounding a virus. Naked, the virus fails to bind and infect cells.

The claims of "Vegetine" were hot air; VITEX, on the contrary, is ready to deliver on its promise of a safer blood supply. The solvent-detergent process has already been in use for more than a decade on factor VIII, a clotting protein given to hemophiliacs. Since 1985, there have been no cases of HIV or transfusion hepatitis transmitted from blood proteins cleaned up by the VITEX method. Before that time, more than half of hemophiliacs who received transfusions were infected with HIV. This spring, VITEX expects its first commercial product, SD-frozen plasma, to be approved by the FDA. It will be marketed under the name of the American Red Cross, which supplies half of the nation's blood products.

The next targets are red cells and platelets, the more fragile blood components. VITEX zaps viruses with a carefully controlled chemical reaction: Light-sensitive phytochemicals are switched on by red light, releasing oxygen radicals that attack viral DNA. Red cells are naturally protected against most of these toxic oxygen radicals, but protective antioxidants in the mix serve as a buffer.

VITEX is also manufacturing sophisticated biological glues that may take the place of surgical sutures. Blood safety is of special concern here, since such products would be derived from two clotting factors--fibrinogen and thrombin--pooled from the plasma of many donors, which increases the risk of virus transmission. "We're exploiting the body's own natural system for healing wounds," says Horowitz. Since the body interprets the biological stitches as natural, they don't raise the ire of the immune system.

Phase II trials in breast cancer patients who had undergone lumpectomy showed speedier healing with surgical glues than with standard sutures. In the future, VITEX hopes to enhance wound healing by adding growth factors and antibiotics, and to refine chemotherapy by delivering a higher concentration of drug directly to a tumor site while limiting the exposure of healthy tissue to the toxic agent. Encasing these drugs in liposomes could achieve slow, sustained release as each layer of the fat molecule dissolves.

Second skin, second chance: Ortec
Nearly 27 years ago in Australia, Mark and Rochelle Eisenberg began a quest recalling the film "Lorenzo's Oil" when their son Ari was born with a blistering disorder of the skin, epidermolysis bullosa. Caring for these children is like caring for permanent burn patients; skin blisters and flakes like tissue paper. Told their son would die in a few years, the Eisenbergs refused to accept the verdict. "They went on an odyssey," says Ortec International president Steven Katz, a relative. They read medical textbooks, looked up every article they could find, and traveled the globe to meet with researchers.

By age 5, Ari's fingers were knit together like mittens, and a surgeon had to slice them open and restore the use of his hands with skin grafts. As Ari grew older, with diminishing healthy skin that doctors could harvest to patch his wounds, his father, an M.D. in general practice, developed a biologically active wound dressing, a cultured skin grown from the foreskins of newly circumcised infants. Tired of attending fund-raisers to support his research, and convinced that others could benefit, he teamed up with Katz to commercialize the technology. Today, Ortec manufactures rosy squares of tissue, which promise a better life for burn victims and diabetics with ulcers, as well as for Ari. In 1996, Ortec went public.

The core product, composite cultured skin (CCS), comprises collagen seeded with immature precursor skin cells. These fibroblasts and keratinocytes secrete a potent cocktail of growth factors, which signal the body's skin cells to proliferate and fill in the wound site. "It's a catalyst that signals the body to heal itself," says Katz. "There's a hole over here. Send in the troops."

From a postage stamp of donated foreskin screened for viruses, immature epidermal and dermal cells are harvested, multiplied 1,000-fold, cryopreserved, and applied to the top and bottom of a bovine collagen matrix. Without sutures or staples, CCS is placed on the wound site. Gradually, CCS stimulates the body's own skin to regenerate. Since CCS is quickly replaced by the body's own skin, there has been no sign of rejection.

EB patients and burn victims alike face long, painful, and costly treatments. Healthy skin is grafted from elsewhere on their bodies, causing pain and additional scarring. In cases of severe burns where the patient's own skin doesn't suffice, cadaver skin is sometimes used to seal the wounds, but cadaver skin may be in short supply, may fail to take hold, or may harbor viruses. CCS has several advantages: Autografts are unnecessary, reducing pain and risk of infection; unlimited quantities are available; accelerated wound healing shortens hospital stays; and scarring may be less severe. CCS is now in clinical trials at burn units like New York Hospital-Cornell Medical Center and in trials for patients with EB or diabetic ulcers. Ortec's primary focus is secondary burns, the most common type, which represent a $350 million dollar market.

Straight to the source code: GenQuest
Today, American men have a 1 in 2 lifetime risk of developing cancer; for women the risk is 1 in 3. The good news is that discoveries like those of Columbia molecular biologist Dr. Paul B. Fisher are bringing us closer to treatments more specific and less toxic than traditional chemotherapy and radiation. GenQuest, a firm founded by Fisher, has a novel approach to ferreting out genes that may one day prove useful in the early diagnosis and treatment of melanomas and breast, prostate, and other cancers.

Those genes could lead to biotherapies with fewer side effects, such as monoclonal antibodies, gene therapy, or vaccines against cancer cells. "I think cancer will be more than a treatable disease in the future," says Fisher. "In five to 10 years there will be therapies that people only think of now as science fiction."

Some large genomics companies sequence thousands of genes before pinpointing their function. GenQuest works in reverse. Vice president Neil Goldstein attempts to describe their approach in simple terms: "We use biology to give us an idea of the actual function of a gene first. Instead of isolating a lot of genes and trying to figure out where in the forest the pot of gold is, we want to get the gold right away and figure out how to spend it." Spending it means partnering hot genes and gene products with companies holding expertise in, say, cancer vaccines, like Seattle-based parent company Corixa. "The gene determines where we will be," says Fisher.

One hot prospect with both therapeutic and diagnostic potential is PEG-3, which Goldstein admiringly calls a "kick-ass" gene. PEG-3 answers the fundamental question of why some cancer cells become aggressive, growing out of control, while others remain benign. This is the first gene shown to be active in cancer progression. What's really exciting is its therapeutic potential: Using antisense technology in rats, Columbia and GenQuest researchers demonstrated that they could reverse a cancer cell's aggressiveness. The gene could also help pathologists with the difficult task of staging a cancer and deciding on the intensity of treatment.

Another useful gene is MDA-7, a tumor suppressor gene just licensed to a gene- therapy company for the potential treatment of prostate and lung cancer. Researchers showed that gene therapy with MDA-7 could both prevent and treat actively growing human breast tumor transplants in an animal model. Phase I trials in humans are slated to begin next year. And GenQuest has a stable of 50 other genes with similar potential, such as the oncogene PTI-1. This gene is expressed in prostate cancer cells, but not in normal prostate or benign prostate hyperplasia, a condition that affects 50 percent of men over age 50. This discovery could lead to the development of better detection, monitoring, and treatment of prostate cancer, the second leading cause of death in American men. In a paper published in February 1998 in Proceedings of the National Academy of Sciences, they reported that cancer cells regained a normal phenotype when PTI-1 function was blocked with antisense technology.2 But Fisher isn't stopping at cancer. He's also looking at genes and gene products that could be used to treat neurodegenerative conditions such as Alzheimer's disease and stroke.

Why work at a new company? Excitement is part of it--"but there's always the possibility of failure," admits Goldstein. Looking back at days spent working for huge drug conglomerates, though, he has no regrets. At one corporation, "I had my boss, who had his boss, who had his boss. There was no way of getting notoriety or affecting decisions about the science. That's the beauty of a small company." Wealth, fame, creative freedom--not too different from the dreams performers have always had at Audubon, be they Hollywood entertainers or New York biologists.

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1. Williams AE, Thomson RA, Schreiber GB, et al. Estimates of infectious disease risk factors in U.S. blood donors. JAMA 1997; 277:967-972.

2. Su Z-Z, Goldstein NI, Fisher PB. Antisense inhibition of the PTI-1 oncogene reverses cancer phenotypes. Proc Nat Acad Sci 1998; 95:1764-1769.

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Columbia University Pathology Department

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RUTH COXETER is a free-lance science and business writer and an associate producer for NBC News.