Human Blood Substitute May Come From Cows
This fall, in an attempt to answer one of medicine’s oldest challenges, scientists at Boston’s Massachusetts General Hospital will apply for permission to drain some blood from human volunteers and replace it with a substitute made from cow’s blood.
If the test and subsequent larger trials show promise, blood researchers and health officials say the fake blood could be widely applied, alleviating the growing strain on the nation’s blood supply. Military medical experts say it could also prove invaluable on the battlefield. A substitute needing no refrigeration that could be stored indefinitely could be taken to the front lines by every medic.
The proposed experiment, sponsored by Boston’s Biopure Corp., is the result of tests on various species, from rabbits to baboons, that concluded hemoglobin--the oxygen-carrying molecule common to all blood--taken from cattle and chemically treated and purified might work in humans. Cattle are considered a good source because so many are killed for meat and vast quantities of bovine blood go to waste.
The appeal of artificial blood, which has been a “Holy Grail” for hematologists for almost a century, lies in its simplicity. Normal blood performs a variety of functions, everything from warding off infection to healing wounds.
By contrast, blood substitutes are designed to duplicate only the most critical of those duties: the oxygen-carrying role performed by hemoglobin inside red blood cells.
Blood substitutes are free of the red cells, white cells, plasma and other biological matter that makes blood a very complex organ. A stripped-down hemoglobin replacement does not risk transmitting new diseases, for example. It also does not need to be matched by type with the recipient before a transfusion and it is potentially much easier to store and administer.
Because of their limited function and the fact they break down in the bloodstream in about a week, substitutes cannot stand in for real blood in all cases. But in medical emergencies and certain surgical applications, blood substitutes are considered to be potential lifesavers.
For example, a patient scheduled for surgery might have some of his blood removed the night before the operation and replaced with the substitute. The fluid that bleeds during the operation would be the substitute and the patient’s blood could be readministered during or after the surgery.
“There is a generally held conviction in trauma management that if a person has sustained a blood loss, the faster you can restore the oxygen-carrying capacity to the bloodstream, the better they are going to do,” said Col. John Slaughter, head of the U.S. Army combat casualty care program that has been looking into blood substitutes for battlefield use since the end of the Vietnam War.
Attempts to find a replacement for red blood cells, however, have been complicated over the years by the difficulty of mimicking the precise role of hemoglobin, a structure of four protein molecules called globins, each enclosing a heme molecule that holds an iron atom that does the actual grabbing and releasing of oxygen molecules.
Human hemoglobin, for example, cannot simply be extracted from donated blood and transfused into patients. Without the protective membrane of the red blood cell, the hemoglobin molecule would disintegrate as it hit the bloodstream, its four sub-units falling through the filters of the kidney before it had the chance to do any good. While hemoglobin alone can pick up oxygen in the lungs, it needs the help of its red-blood-cell host to drop it off in the appropriate organs.
These difficulties led researchers to begin their search with chemicals from the perfluorocarbon family, of which Teflon is a member. The chemicals share with hemoglobin the ability to take up and deliver oxygen on demand. The problem is that perfluorocarbons, at least in initial tests, cannot carry nearly as much oxygen as hemoglobin.
So researchers returned to human hemoglobin, looking for chemicals that could increase the survival time of hemoglobin in the bloodstream and make it easier for the molecule to deliver its oxygen payload at the appropriate moment.
Problems Solved
Researchers at two U.S. companies, Baxter Healthcare Corp. and Northfield Laboratories, appear to have solved those problems, but they still face a more serious one. They hope to use outdated human blood from blood banks as a raw material. But it appears that too little blood can be obtained this way to meet the potential demand.
One solution might be to use the techniques of genetic engineering to clone the human hemoglobin gene, then simply grow the molecule in massive fermentation tanks the same way that some new drugs are produced. But the technical hurdles of such an approach are formidable.
“Right now the cost of recombinant production is such that it is only efficient in terms of high value trace proteins,” said Leon Hoyer, national research director for the American Red Cross Blood Service.
“You need such huge volumes (of hemoglobin) that I would be very surprised if it could be produced at a reasonable cost.”
The supply questions have focused many researchers on the potential of using cattle as a hemoglobin source.
But here, as with human hemoglobin, preparation is difficult. Biopure, the leader in attempting to commercialize the compound, first filters and then uses chemical techniques to separate any red-blood-cell membrane, which can cause fever, from the hemoglobin.
Even the slightest contamination could have serious consequences during human administration, because little is known of the possible toxins in bovine blood.
Bovine hemoglobin also must be stabilized to prevent breakdown of the hemoglobin molecule once it enters the bloodstream. For this, researchers rely on a technique similar to preparing human hemoglobin. The four sub-units of the hemoglobin molecule are bound by chemical bridges, permitting the hemoglobin to survive a week in the bloodstream.
The critical question for bovine hemoglobin, however, is how the body’s immune system will react to the infusion of an entirely foreign compound.
In other animal tests, Biopure replaced as much as 90% of the blood of a sheep without triggering a severe immune response. Monkeys infused with bovine hemoglobins sustained only a mild immune response.
In humans, some researchers have speculated that the effect of the bovine extract will be similar to that of bovine insulin, which long has been used by diabetics. It is biologically similar enough to human insulin that it rarely produces side effects.
Another possibility is that bovine hemoglobin might trigger an immune response, but only after repeated transfusions, which might not be a major hindrance for selected use in trauma cases.
“Bovine (hemoglobin) has a virtually unlimited supply and the data suggests that it is a good oxygen carrier,” Hoyer said.
“But they are going to have to get around everyone’s prejudice, right or wrong, that it will stimulate an immunological reaction.”
