Scientific American: Feature Article: Saying Yes to NO: November 2001

Saying Yes to NO

The patent office is issuing a wealth of patents related to one of the most celebrated molecules of the past decade.

By GARY STIX

JONATHAN STAMLER of Duke University has applied for more than 50 NO-associated patents.

SAM OGDEN

When three Americans won the Nobel Prize in Physiology or Medicine in 1998 for discoveries about nitric oxide, news coverage often focused on how this insight helped lead to the creation of Viagra. But the ubiquitous role that nitric oxide (NO) plays in the body--it does everything from fighting infections to combating cancer--has spurred a gold rush of patenting. One prominent researcher, Jonathan Stamler of Duke University and the Howard Hughes Medical Institute, has received more than 10 patents in the past 18 months alone for his work on NO; he estimates that he has applied for more than 50 in all.

A key recent patent relates to basic research performed by Stamler and his colleagues. The work showed that hemoglobin, besides shuttling oxygen to tissues and retrieving carbon dioxide, also delivers NO. Before, scientists had always believed that hemoglobin destroyed NO.

The new research demonstrated that the NO linked to hemoglobin allows blood vessels to expand or contract, depending on how much of the molecule is present. Patents received by Stamler and his colleague Joseph Bonaventura (U.S.: 6,153,186 and 6,203,789) provide a method for restoring NO in red blood cells that have been depleted through disease or while being stored in blood banks. The NO binds to cysteine, an amino acid in hemoglobin, to form a molecule called an S-nitrosothiol. When the red blood cells arrive at the capillaries, they release oxygen as well as the S-nitrosothiols. The NO in the S-nitrosothiols dilates blood vessels and thus allows oxygen to better reach tissues. NO-loaded blood cells could boost the effectiveness of blood transfusions done to treat sickle cell anemia and to replenish blood after heart attacks, strokes and other conditions in which tissues suffer from oxygen deficiency.

Another major finding achieved by Stamler's group was that NO binds to transcription factors and enzymes that regulate proteins in invading pathogens and in cancer and other abnormal cells. Stamler and Owen W. Griffith of the Medical College of Wisconsin won patents (U.S.: 6,057,367 and 6,180,824) for fighting microbes and cells gone awry by manipulating NO-related biochemical pathways. When the body is under attack from microorganisms, for instance, mammalian immune cells called macrophages produce NO, which attacks critical metabolic enzymes and other proteins in the pathogens. In a routine counterattack by the microbes, a sulfur-containing molecule, a thiol, wipes up the NO, a first line of defense against the invasion.

One aspect of the patents covers chemicals, such as a sulfoximine (which is related to a cancer chemotherapeutic agent), that inhibit enzymes and transcription factors that synthesize thiols in microorganisms but leave proteins in human cells relatively untouched. In addition, NO can be attached to an anticancer chemotherapeutic agent that homes in on a rapidly dividing cell, thereby enhancing its effects.

Stamler and Griffith's patent coverage is very extensive. Besides new drugs, one of the patents also covers molecules targeted by pharmaceuticals: any protein that microorganisms and other pathologically proliferating cells, such as those in cancer or in reblockage of an artery (restenosis), use to protect themselves against an NO onslaught. "This is a broad-based system, disruption of which may have major implications in biology and disease," Stamler notes. Please let us know about interesting and unusual patents.

Reprinted from Scientific American, Nov 2001