Efforts to develop blood substitutes that could be used to treat soldiers or trauma victims in remote settings have held great promise as a way to infuse oxygen-carrying liquids into patients, thereby saving their lives when real or safe blood is in short supply.

Biotech companies have even come up with long shelf life replacements that would work for all blood types without the need for refrigeration.

The companies developing these hemoglobin-based blood substitutes, however, are now fighting for their own lives—enduring failures and financial hardships in order to stay in business long enough to see their creations come to market. And making matters more complicated, some observers, including the U.S. Food and Drug Administration (FDA), question whether these surrogates do more harm than good—or are even necessary anymore.

On paper, blood substitutes look good. But when hemoglobin (an iron-enriched protein in red blood cells that transports oxygen from the lungs to the rest of the body) is introduced directly into the bloodstream without the protection of red blood cells, the body tends to break down and remove the protein, a process that can be toxic to the kidneys, constrict blood vessels (resulting in hypertension), and cause inflammation. If the blood substitutes are not designed to prevent this hemoglobin purging, they can increase a patient's risk of death or at least some serious complications, including inflammation of the pancreas (which helps the body digest food and produces insulin), elevated liver activity, and heart attack, according to studies assessing the safety of blood substitutes.

FDA advice
In an effort get the development of a safe and effective hemoglobin-based blood substitute back on track, the FDA in April 2008 met with several companies developing these products to deliver a new plan. (pdf) "One of the main messages from that meeting was that the first generation of products was too toxic and should be discontinued, which is what happened," says Arthur Bollon, chief executive of Dallas-based HemoBioTech, Inc., which is working to develop just such a product. "One of the FDA's recommendations was that these substitutes use adenosine-modified hemoglobin, which is the core of what HemoBioTech does." This process of modifying hemoglobin is what makes the company's HemoTech blood substitute nontoxic and anti-inflammatory, he adds.

The FDA put these substitutes for blood's oxygen-carrying capability on hold after determining that the "death rate was significantly higher in the patients who got these solutions, compared with those who got regular blood or nothing at all," says Paul Holland, a clinical professor of medicine and pathology in the Division of Hematology and Oncology at the University of California, Davis's medical center. "The FDA told all companies to go back to the drawing board and come up with better clinical trial designs."

Congressman steps in
HemoBioTech, one of the few companies that is still in business since the 2008 FDA meeting, may have an ally in Rep. Edolphus Towns (D–N.Y.), who earlier this month wrote an open letter to fellow House of Representatives members encouraging them to support funding for a "promising, cost-effective" blood substitute using hemoglobin modified with adenosine. "Fully 10 percent of [HIV and AIDS] infections and deaths can be prevented with a viable blood substitute that can deliver oxygen throughout the body with minimum or no toxicity," he wrote. He asserts that it would take an investment of less than $35 million to get these projects through human trials.

Towns has a history of pushing for measures meant to reduce the risk of AIDS infections. This includes his support in April 2008 to extend and expand the U.S. Global Leadership against HIV/AIDS, Tuberculosis and Malaria Reauthorization Act (pdf), a measure that authorized $50 billion in spending in an attempt to prevent an estimated 12 million new HIV infections as well as provide drugs for three million AIDS patients, medical and nonmedical care for 12 million people (including five million orphans), and training for 140,000 new health care workers by 2013.

The funding Towns is pushing for is extremely important to companies such as HemoBioTech, which are trying to raise money to continue developing and testing their products. "The amount of money that Towns is talking about would carry us into phase III testing and move us very close to commercialization," Bollon says. "We're raising money now to do animal studies that would confirm HemoTech's lack of toxicity. We believe that as soon as we can raise the necessary funds, it could be completed in a matter of six months."

Money is indeed a huge obstacle for HemoBioTech, which has lost more than $16 million since its inception in October 2001. In a quarterly financial report that HemoBioTech sent to the U.S. Securities and Exchange Commission on August 18, the company noted it needs to raise $7 million in the near term just to get the green light from the FDA to proceed with phase I clinical trials. Longer term, the company projects costs of $10 million, $20 million and $195 million to complete phase I, II and III trials, respectively.

Without the money, HemoBioTech could find itself in the unenviable position of several former competitors. Northfield Laboratories, Inc., an Evanston, Ill., biotech that failed to get FDA approval for its PolyHeme hemoglobin-based temporary oxygen-carrying red blood cell substitute, filed for bankruptcy in June. Biopure Corp. likewise filed for bankruptcy in July after the FDA denied the Cambridge, Mass., biotech approval to take its Hemopure substitute to clinical trials.

The impetus for the development of blood substitutes was high in the early 1980s, before blood was screened as carefully as it is today. The chance of being infected by a blood transfusion today is as great as one in 10 million, Holland says. U.S. blood donations have been screened for antibodies to HIV-1 since March 1985—nearly all of the people in the U.S. infected with HIV through blood transfusions received those transfusions before that year. And since June 1992 donations have been screened for antibodies to HIV-2 (the strain of HIV confined mainly to West Africa). The Protein 24 (p24) Antigen test, which checks for the presence of this HIV protein, was added in 1996.

"Maybe 25 years ago this might have been a good idea because of the risk of AIDS or hepatitis infection," Holland says. In San Francisco, circa 1982, the chance of a blood infection was about one in 100. "This was a problem," he adds, "but blood is incredibly safe now."

The products that HemoBioTech and others are pursuing might serve as a "very temporary solution on the battlefield or in a trauma setting," Holland says, but the patient would still eventually need to receive actual blood. "It's a great idea but unfortunately it's past its prime. The bottom line is that [the substitutes] these companies were working on have very limited applications and were actually found to be harmful."

Other options
Still, there are those medical circumstances that call for blood substitutes. And perhaps more promising than hemoglobin-based blood substitutes are experiments under way in the U.S. and France to actually grow new red blood cells from umbilical cord blood, Holland says. "You start with umbilical cord blood, instead of throwing it out [after babies are delivered], and add nutrients so that it grows," he adds.

One of the more promising prospects is Cleveland-based biotech Arteriocyte, Inc., which in November said it had received nearly $2 million from the Defense Advanced Research Projects Agency (DARPA) to assist with the agency's "blood pharming" program, whose goal is to create a donorless supply of universal red blood cells from umbilical cord blood. Arteriocyte—in collaboration with researchers at Johns Hopkins University, The Ohio State University and The French National Institute for Health and Medical Research (Inserm)—is developing the technology to help DARPA do this. (Inserm is a public institution headquartered in Paris that operates under France's ministries of Health and of Higher Education & Research.)