Rice Biochemist Helps Create New, Improved Blood Substitute

Rice Biochemist Helps Create New, Improved Blood Substitute

BY LIA UNRAU
Rice News Staff
July 30, 1998

For most people in an emergency room, having blood available–healthy blood–is
of utmost concern. To guard against shortages and diseases, blood substitutes
are being developed to deliver oxygen to the brain and heart. Unfortunately,
most of the protein-based blood substitutes, now in clinical trials, have an
unwanted side effect–increases in blood pressure.

Researchers from Baxter Healthcare Corp.’s Hemoglobin Therapeutic Division
in Boulder, Colo., (formerly Somatogen Inc.) and Rice biochemist John Olson
have determined why blood pressure increases when hemoglobin-based blood substitutes
are given to animals, and they have engineered new prototype molecules without
this side effect.

"Researchers have known that hemoglobin, the carrier of oxygen inside
a red blood cell, also reacts with nitric oxide, a compound that is required
for maintaining normal blood pressure," Olson says. "When the two
react, the nitric oxide is depleted and blood pressure tends to go up."

Hemoglobins designed to steer clear of nitric oxide may be more suitable for
certain blood replacement uses than those that cause significant loss of nitric
oxide (NO).

Using genetic engineering methods to alter the hemoglobin reaction with NO,
the Baxter team, led by Douglas Lemon, who received a Rice doctorate in 1989,
and Ol-son found that the rate of reaction with NO determines the magnitude
of the blood pressure effect. The faster the cell-free hemoglobin reacts with
the nitric oxide, depleting the reservoir of nitric oxide in the system, the
greater the increases in blood pressure.

Their research appears in the July issue of Nature Biotechnology.

Nitric oxide is found in the endothelial and smooth muscle cells lining the
outer walls of blood vessels. It is thought that because simple cell-free hemoglobins
are small, they slip through the blood vessel walls to react with NO. Researchers
first designed interconnected hemoglobins to increase their size and discourage
passage through the walls.

Olson, the Dorothy and Ralph Looney Professor of Biochemistry and Cell Biology,
said he adopted an alternative strategy to this problem: figure out the chemical
mechanism of the reaction with nitric oxide and then genetically engineer the
hemoglobin to inhibit the process.

"We needed a way to keep the bound oxygen molecule from reacting with
nitric oxide and the iron atom from rusting," Olson says, "so we placed
a protective film of large oily amino acids around them."

Says Lemon: "When the engineered hemoglobin molecules were tested in rats,
the blood pressure increase was proportional to the rate of reaction with nitric
oxide. At the lowest reaction rate, the blood pressure effect was nearly eliminated."

It is possible that other side effects sometimes seen in clinical trials with
blood substitutes, such as gastrointestinal dysfunction, are also based on nitric
oxide depletion and inhibition of smooth muscle relaxation, making the new prototype
molecules attractive choices for a second generation blood substitute.

For related information visit the following Web site:
Department of Biochemistry and Cell Biology: http://dacnet.rice.edu/~bioc/