Science/Medicine : Blood Substitutes : Quest for a Wellspring of Life
Stick a sterile pin into a fingertip and out comes a drop of your precious blood--precious because in just that tiny amount there are between 250,000 and 500,000 red blood cells from the “river of life” coursing throughout your body, carrying oxygen to and carbon dioxide from all your other body cells.
You won’t miss that drop, really, because your bone marrow normally produces (and you lose) about 300 billion red cells every day--and that’s only about 1% of the total number in your body.
If those numbers stagger you, consider that the red blood cell is the smallest in the human body. Its pinched, disc-like shape, size and flexibility enable it to travel through your arteries, veins and the tiniest of capillaries in between as it goes about its vital business.
In the absence of the oxygen it delivers to the body’s cells, life would end in a few minutes. There is oxygen dissolved in the plasma (the liquid portion of the blood), but the red cells and their oxygen-holding protein, hemoglobin, carry about 99% of that life-sustaining gaseous element.
For more than 20 years now, researchers have been trying to find a safe and effective substitute for the red blood cell. But only recently has the research reached the stage of human clinical trials.
The advances come at a time when there is perhaps unprecedented concern about the purity of the nation’s blood supply--spurred in large part by the AIDS crisis.
A blood substitute, then, would find widespread use.
Each year, about 4 million Americans receive blood transfusions, and 250,000 of them end up contracting hepatitis. A blood substitute also would greatly simplify transfusions by obviating the need to match the blood type of the recipient. In addition, a blood substitute would be a literal lifesaver in parts of the world where there are few blood banks, and in the treatment of trauma victims.
Many experts believe that the goal is within reach, but there are just as many who are convinced that it remains as elusive as ever.
The intensifying effort involves multibillion-dollar pharmaceutical companies, comparatively small and thinly financed independent laboratories, and scientific teams in both commercial and academic settings around the world.
Researchers are working on two approaches to the problem. One method uses chemical compounds known as perfluorocarbons, and the other involves the extraction and linking of hemoglobin molecules from natural red blood cells.
Perfluorocarbon chemicals--the Freon in today’s refrigerators and aerosol propellents are examples--have been under study for more than 20 years. They can be formed into emulsions of particles suspended in ultramicroscopic dimension and capable of carrying oxygen to body cells while taking away their carbon dioxide waste, thereby imitating the role of hemoglobin, in part at least.
The promise of perfluorocarbons was demonstrated in experiments in 1966-67 during which the blood of a dozen laboratory mice was completely drawn off and then replaced for a few hours with oxygen-laden fluorocarbon liquids and water.
Dr. Leland Clark, who performed this and other pioneering experiments at the University of Cincinnati, reported that the lungs and other organs of his mice showed no damage after they subsequently lived out their normal life spans. His work demonstrated the potential of perfluorocarbons in the life-essential oxygen-carbon dioxide exchange.
However, perfluorocarbon particles carry less oxygen than hemoglobin, and recent clinical trials have indicated that their usefulness as a red-cell substitute, except in specialized treatments, is marginal. They can be prepared in higher oxygen concentrations, but at some risk to the lungs.
These perfluorochemical particles can be made at about 1/70th the size of red blood cells, according to the maker of Fluosol, Los Angeles-based Alpha Therapeutic Corp., a U.S. subsidiary of Green Cross Corp. of Osaka, Japan.
A thin, milky fluid that must be kept frozen until used, Fluosol has been tested extensively in humans and laboratory animals in Japan and this country over a period of years and has proved to be useful in certain coronary surgical procedures, cancer radiotherapy and chemotherapy. It was precisely because of their oxygen transport capabilities and incredibly ultramicroscopic size that perfluorochemical emulsions came to the attention of heart surgeons and cancer radiologists.
In balloon angioplasty, in which plaque-clogged arteries are opened by the inflation of a tiny balloon inside the blood vessel, blood flow to the part of the heart the artery serves is interrupted; pain and damage can result. But because of the tiny size of the perfluorocarbon particles, the use of Fluosol can assure the continuing flow of oxygen through the heart muscle and thus avert possible disaster, according to recent reports in medical journals.
In cancer therapy, the oxygen levels in tumor cells are characteristically lower than normal cells, since the tumors have destroyed many of the capillaries by which red cells reach them. This oxygen lack within the malignant mass makes the tumor cells far more resistant to radiation therapy, and is seen by some investigators as hindering chemotherapy in certain tumors as well.
Researchers have turned to perfluorochemical emulsions in recent years to find ways to get oxygen into those cells, thereby increasing the effectiveness of radiation and chemotherapy treatments.
Meanwhile, the ultimate aim for other research scientists continues to be a hemoglobin preparation that can be stored, perhaps as a powder, under myriad conditions in any part of the world, and quickly reconstituted in enormous quantities as needed.
Sometime before the closing days of 1987, six pairs of adult volunteers are to receive a transfusion either of a hemoglobin substitute or, as a comparison group, of fresh whole blood in a test directed by Dr. Gerald Moss, chairman of surgery at Chicago’s Michael Reese Hospital.
Actually, this will be the second human trial using so-called polyhemoglobin produced by Northfield Laboratories. The first test took place earlier this year and resulted in failure when the volunteer experienced a temporary allergic reaction after the transfusion.
Polyhemoglobin is comprised of a short chain of two or three hemoglobin molecules taken from red blood cells, then treated to destroy bacteria and viruses (including the AIDS agent), and finally incorporated into a solution capable of storage “for extended periods,” according to a lab spokesman.
Northfield’s polyhemoglobin is believed to be the only product of its kind at this stage of clinical evaluation, although it is probably several years away from commercial availability, he concedes.
The search for a safe, effective blood substitute has been a longtime objective of the Army, said Col. Robert M. Winslow, hematologist and chief of the blood research division at Letterman Army Institute of Research in San Francisco. The Army’s term for such a preparation is “resuscitation fluid.”
Scientists of the huge Baxter Health Care Corp. have developed two versions of polymerized hemoglobin molecules under Army contract at laboratories in Glendale and Duarte. Neither version shows signs of harmful reaction in laboratory experiments, Winslow said, and work is building up to human trials in about 18 months.
While both the perfluorocarbon and polyhemoglobin lines of study have their advocates, most hematologists in the United States view these efforts with caution, if not downright skepticism, at least for now.
“The published data about Fluosol suggest it has little or no effect in acute anemia, and I know of no clinical studies with cross-linked hemoglobins that would allow one to judge whether or not they are effective. Versions of these two technologies might prove to be useful someday, but this remains to be shown,” said Dr. Ernest Beutler, an expert on red blood cell preservation and chairman of the department of basic and clinical research at Scripps Institute in San Diego.
While blood substitutes have advanced to the point of sustaining patients in short-term critical situations, Beutler admits, he insists that “man will never emulate nature completely in his attempts to replace the red blood cell--one of the most complex of all living cells.”
The Experiment
The most well-known experiment in the quest for synthetic blood--which demonstrated the potential of perfluorocarbons in the life-essential oxygen-carbon dioxide exchange--was conducted by Dr. Leland Clark of the University of Cincinnati.
Clark filled a beaker with silicone oil laced with perfluorocarbons and then dropped mice into it. As with any drowning animal, the mice’s lungs filled and they sank. But they continued to breathe. After the mice were withdrawn, they lived with no apparent damage to lungs or other organs. Under normal conditions, a blood substitute would remain in the circulatory system and not fill the lungs, said Clark.
The Blood Cell
The red blood cell is the smallest in the human body. Its pinched, disc-like shape, size and flexibility enable it to travel through arteries, veins and the tiniest of capillaries. Virtually all of the oxygen needed by the body is carried by the red cells.
