Science & Technology: MEDICINE
ARTIFICIAL BLOOD MAY BE A HEARTBEAT AWAY
Richard DeWoskin's quest began in 1970, as critically wounded American soldiers were bleeding on the battlefields of Vietnam. A young biology student at the time, DeWoskin was recruited by prominent Navy surgeon Dr. Gerald S. Moss to help develop artificial blood for the U.S. military.
It was the start of a roller-coaster ride from discovery and breakthrough to the brink of despair. Now the company they started, Northfield Laboratories Inc., may finally be nearing its goal: to create an inexpensive, abundant, and safe replacement for hemoglobin--the oxygen-carrying component in red blood cells. "Our work is finally paying off," says DeWoskin, now chairman and CEO. "We're not that far away."
A half-dozen other biotech and medical equipment companies--including giants Baxter International, Upjohn, and Eli Lilly--have targeted similar types of products. But recently, the Evanston (Ill.) startup has pulled ahead in all-important "Phase II" trials to establish efficacy and safety. If it can pass a final cluster of tests, Northfield's product, called PolyHeme, could be on the shelves in 1997.
HYPOGLOBIN. A dose of skepticism couldn't hurt, however. Over the past decade, more hype than hemoglobin has issued from science labs in America, Europe, and Japan--and Northfield has been no exception. The fact is, human blood is fiendishly difficult to duplicate. And hemoglobin is the biggest challenge of all. This iron-bearing protein, which makes blood red, binds oxygen and ferries it to tissues throughout the body. Massive blood loss quickly leads to oxygen deprivation, followed by shock and failure of vital organs.
Physicians can bolster a patient's blood levels temporarily with salt or protein solutions that keep the heart pumping. But these can't deliver critical oxygen. Transfusing donated blood solves the problem but has clear disadvantages. It must be matched to the patient's blood type, which wastes precious time. It is prone to viral contamination, as the AIDS epidemic has demonstrated. And it has a short shelf life--just 28-42 days.
Consequently, blood is almost always in short supply. More than 4 million Americans receive upwards of 12 million units of it each year. But recently, supplies have dwindled because the AIDS menace, illogically, has scared away many potential donors. So-called blood substitutes, on the other hand, won't carry diseases or need to be cross-matched. And in theory, they can be stored safely for up to one year. As a result, the market for substitutes could run as high as $2.5 billion a year, according to analysts at Robertson Stephens & Co. in San Francisco.
AGAINST TYPE. The stumbling block for scientists has been retrieving and isolating the 280 million hemoglobin molecules contained in each red blood cell so that they can be transfused no matter what a person's blood type is. Removed from a protective cell casing, however, the molecules tend to leak through the blood vessel wall into surrounding tissue. Unless they are genetically or chemically altered, the molecules can be toxic to nearly every organ in the body.
To get around that, companies have adopted several exotic approaches (table). Upjohn, in a partnership with Boston-based Biopure, is testing hemoglobin from cow's blood that is rejiggered to avoid attack by the body's immune system. Somatogen Inc. in Boulder, Colo., working with giant Eli Lilly & Co., is producing hemoglobin from genetically altered bacteria. Others hope to bypass nature's own mechanism entirely. San Diego-based Alliance, backed by Johnson & Johnson, is developing a substance based on nontoxic, oxygen-carrying chemicals called perfluorocarbons. Such substances have produced side effects, but Alliance has reformulated them to smooth the body's acceptance.
Northfield's approach is less technologically ambitious and may, therefore, be easier to perfect. Scientists begin by removing red blood cells from donated blood that has sat on a shelf longer than the time permitted by the Food & Drug Administration. Since expired blood has no other medical uses, Northfield can obtain it cheaply. Next, they extract hemoglobin molecules and link them together in long chains, called polymers. Their larger size prevents them from leaking from the blood vessels. The resulting solution is purified and bottled, giving it a long shelf-life.
This approach isn't entirely new. Northfield used similar techniques in the mid-1980s to produce its first experimental substitutes. Unfortunately, these caused breathing difficulties and muscular pains in some test patients and had to be withdrawn from FDA trials in 1990.
Northfield says the problem was caused by naturally occurring contaminants the company had overlooked. With stepped-up purification, the symptoms disappeared. In March, Northfield received FDA approval to double its dosage of PolyHeme in ongoing human safety trials to 300 grams or six units--about three-fifths of the total blood in the human body--an unprecedented high level in the field of blood substitutes and about what might be required in a severe accident. Northfield's closest competitors, Baxter and Somatogen, have had difficulty moving beyond 30 grams in similar phase II trials. "Northfield has jumped way ahead," says Kevin C. Tang, a biotechnology analyst with Alex. Brown & Sons Inc. Investors are also pleased. The stock is trading at 13, double the price it listed at a year ago.
That doesn't mean the battle is over. "There are still a lot ef fundamental questions that need to be answered," says Dr. Joseph C. Fratantoni, the FDA's chief medical reviewer for blood substitutes. Because of earlier safety problems--Northfield's and others'--the FDA remains wary of blood substitutes in general, and has yet to lay out specific endpoints for Phase III trials that establish efficacy and dosage. Says Fratantoni: "We've already got a product that's satisfactory in both safety and efficacy"--donated blood.
TRIAL TRIALS. Northfield's biggest problem is time. Even analysts who admire its prototype admit that Northfield may not have deep enough pockets for a prolonged Phase III trial. Unlike its larger and more diversified competitors, the company has no other products on the market or even in the pipeline. DeWoskin maintains that the need for a cash infusion is not immediate. The company has $12.5 million in the bank--sufficient to cover the next 20 months of expenses. "We're not strapped from an operating standpoint," he insists.
Expanded clinical trials and increased manufacturing will cost Northfield $25- $30 million, but DeWoskin and President Steven A. Gould believe they can sign up a partner--preferably a large pharmaceutical company that will trade cash and production capacity for PolyHeme marketing or distribution rights.
For DeWoskin, hashing out such deals is a minor detail compared with the enormity of proving the science--and helping patients. Since the 17th century, he notes, researchers seeking blood substitutes have tested everything from milk and vegetable oil to beer. If he can keep Northfield on track, they may be breaking out the champagne.By Ron Stodghill II, in Evanston, Ill.