Researchers developing synthetic blood face a troubling dilemma. Lives saved in the short term could ultimately be lost to a harsh side effect of these products: high blood pressure. A group of US scientists believe they are on the way to solving the problem.
The solution, published in today's edition of the journal Nature Biotechnology, involves a chemical sleight of hand in the walls of the body's veins and arteries. Blood vessels are lined with smooth muscles that open and constrict, depending on how much of the compound nitric oxide is present. The more nitric oxide in the muscle tissue, the less likely it is for the vessel to constrict.
"By engineering a lower rate of reaction [between the blood product and the nitric oxide], the less there is of a blood-pressure effect," said Douglas Lemon, a scientist with Baxter Hemoglobin Therapeutics.
To keep nitric oxide levels high, Lemon and his colleagues dealt with one of the stickier issues of developing synthetic blood products. Real blood carries oxygen to the body through hemoglobin, a protein inside red blood cells. By contrast, synthetic blood is a laboratory-brewed form of hemoglobin, with no blood cell surrounding it, so the protein is free to react with whatever it comes into contact. Herein lies the problem: Hemoglobin gobbles up nitric oxide.
"The vessels inside the rats decreased in size a bit, and we saw it manifesting itself in higher blood pressure," said Lemon, who was a co-author on the paper.
The key to reversing the situation is to build a better, less reactive hemoglobin. Lemon said he and his colleagues engineered a new variant of hemoglobin using bacterial synthesis, where the fast-growing qualities of a bacterium are turned into a type of factory. Lemon and his colleagues used one of the best known bacteria -- e. coli -- to make the mutated hemoglobin. They tinkered with the hemoglobin-producing genes to make them absorb less nitric oxide, then implanted the genes into the bacteria.
This new hemoglobin appeared to absorb less nitric oxide in the laboratory rats, Lemon said.
Lemon's work has given researchers some hope. "[Nitric oxide absorption] is the last major boundary to developing synthetic blood," explained Robert Winslow, professor of medicine at the University of California at San Diego.
The problems Lemon's group is trying to combat illustrate the metabolic, toxicological, and physiological hurdles that researchers must clear in developing their products, said Winslow. Synthetic-blood development is a tricky proposition. Already this year, Baxter Hemoglobin Therapies has halted US trials of its own synthetic-blood product, HemAssist, because of high mortality rates among trauma patients using the product. It suspended tests in Europe last month after the product was found to have little effect.
"If anyone knew 50 years ago how difficult it would be [to develop synthetic blood], no one would have tried it," Winslow said.
Even with Lemon's breakthrough, questions remain. Lemon's work establishes a cause-and-effect connection between the mutated hemoglobin and the nitric oxide. There is no shared vision that one thing alone causes the constriction of blood vessels, noted Winslow, who is working on a synthetic-blood project as well.
Winslow's work builds on the idea that the absence of a cell to carry the hemoglobin means that the oxygen it carries is also free flowing in the body. Winslow sees the vasoconstriction as a reflex that is susceptible to the ebb and flow of oxygen in the vessel. The higher the level of oxygen, the more likely the muscles are to constrict.
And this poses a problem for Lemon's work. "If you design a mutant to exclude nitric oxide, it will exclude oxygen as well," Winslow said.
