Issue 1, June 2004

Finding Hemo: Do we need fake blood?

Jessica Tanenbaum, Science Journalist
Molecular biochemistry and biophysics, Yale University
tanenbaum@jyi.org

Figure 1. Blood safety testing. The FDA requires a variety of tests before blood banks may deem collected blood as safe for transfusion. Blood is tested for HIV, syphilis, hepatitis, and blood type. Uniform Labeling Guidelines enforced in 1986 confirm test results. Source: Centers for Disease Control and Prevention.

“False blood to false blood join’d!” cries Constance in the second act of Shakespeare’s The Life and Death of King John. Shakespeare was not anticipating the current struggle to design an artificial blood substitute when he wrote this line. In fact, Shakespeare died even before William Harvey explained how blood circulates in 1628. But appreciating the ancient history of blood’s metonymic association with life offers some explanation of the urgency and misinformation surrounding the search for blood substitutes.

“False blood” usually connotes disloyalty, illness, and vice. But recently, scientists have been creating new meanings for false blood: safety, efficiency, and heroic capabilities. Today, efforts to create blood substitutes show promise as hospitals begin limited trials of these vital products.

People unfamiliar with the complex field of hematology, the science of blood, may scoff at the delay. They may ask, “If science could create Dolly the cloned sheep in 1997, then why hasn’t it also created fake blood?” Dr. Thomas Ming Swi Chang, of McGill University, began a recent article in Artificial Cells, Blood Substitutes, and Immobilization Biotechnology by acknowledging, “We all feel humble in the face of the ingenuity and complexity of nature.” Blood, it seems, is no simple liquid.

Creating artificial blood would do more than boost the egos of bioengineers and hematologists. One American needs a blood transfusion every two seconds; if this person is lucky, he will receive blood from a well-stocked blood bank. But blood transfusion and the blood banking business carry along with them a complex set of problems that artificial blood could avoid.

First of all, donated blood does not stay fresh. Red blood cells, the constituent of blood in highest demand, has a fridge life of 42 days and a freezer life of 10 years. Every year, blood banks pay to keep 15 million units of blood cold during storage, testing, and distribution. Anyone who pays an electricity bill will understand the huge price tag attached to this refrigeration. And just like December’s milk in January, expired blood gets thrown away.

Though blood banks cannot get all their donated blood to needy veins, they still fail to satisfy the enormous demand for blood. Trauma victims, patients undergoing surgery, and people with sickle cell disease and other afflictions all create a huge need for transfusions. And with baby boomers in America continuing to age, the need for blood only increases.

Another factor in the search for blood substitutes comes from an ancient human motivator: fear. This fear has been partially tamed in recent years. As screening methods advance and the Food and Drug Administration (FDA) assumes an increasing role in assuring blood safety, probabilities of receiving bad blood plummet. In 1987, scientists estimated that 1 in 250,000 patients would contract HIV after a blood transfusion. Today, that risk is 1 in 2,135,000. Donated blood undergoes testing for HIV, hepatitis B, hepatitis C, syphilis, and a host of other diseases. Safety has been increasing ever since 1667, when Jean-Baptiste Denis first transfused animal blood into human veins.

Figure 2. These round red blood cells, or erythrocytes, contain hemoglobin, an oxygen-carrying molecule. Hemoglobin binds to oxygen with its four iron atoms. The iron gives blood its red color. Source: Brian Garrigan, www.garrigan.net

Even with decreasing risks, blood supply safety remains a pressing issue. The American Red Cross turns away donors who have received a blood transfusion in the United States within the last year. Potential donors who received transfusions in many foreign countries since 1980 are no longer eligible. Dr. Paul M. Ness, a professor of pathology and medicine at Johns Hopkins University and a former employee of the American Red Cross, explains, “the standards for blood donation are made very conservatively in this country.” The slight risk of infection from receiving a transfusion justifies this post-transfusion donation refusal.

Emerging diseases present another problem for blood supply safety. Today, patients are at low risk for contracting HIV from a transfusion because community anxiety and focused medical attention inspired policy change. But what if a new infectious disease taints the nation’s blood supply? In the last decade, the blood supply labeling system has made it possible to enact a rapid recall if bad blood gets out. However, recalling thousands of units of blood could create a dangerous blood shortage, and the FDA would have to know about the contaminant, an unlikely recall condition for new and therefore undetected diseases.

Artificial blood substitutes may boast of one final advantage over real blood. Because blood substitutes would have no blood type associated with them, they would help level the playing field for people with rare blood types. A stay-fresh, abundant, purified, and universally accepted blood substitute eliminates the small risks and great anxieties associated with blood transfusion. So why the hold-up?

By 1959, with the help of X-ray crystallography, Dr. Max Perutz of Cambridge University had elucidated the structure of hemoglobin, the four-subunit protein responsible for toting oxygen through the body. In introductory biology, students learn that hemoglobin carries oxygen to the body’s tissues and takes away their used carbon dioxide. From an engineering standpoint, that task should be easy for a synthesized molecule.

At the beginning of the search for blood substitutes, scientists thought they could give extra hemoglobin to patients short on blood. This easy solution would be safer than blood transfusions because spare hemoglobin has no immune response-inducing blood type. But scientists discovered early on that they can’t just add extra hemoglobin to blood to transport oxygen. Without a red blood cell, hemoglobin is unstable and falls apart. The useless hemoglobin accumulates in the kidneys and causes significant health problems. Clearly, creating a blood substitute would not be a simple task.

As biomolecular research advanced, scientists began to better understand hemoglobin’s function. Hemoglobin, which sits inside Cheerio-shaped red blood cells, undergoes functional changes because of these cells. Pure hemoglobin binds oxygen with too much enthusiasm, unwilling to share its oxygen with needy tissues. Coupled with a red blood cell, hemoglobin willingly trades oxygen for carbon dioxide in the low-pressure environment of the veins.

Some efforts to create artificial blood modify hemoglobin to enhance function and avoid subunit dissociation. Scientists keep hemoglobin in one piece by chemically linking it to other hemoglobin molecules. PolyHeme and Hemopure, two of these polymerized hemoglobin products, are currently undergoing Phase III clinical trials in human patients. But because of pure hemoglobin’s other problem — failure to adequately release oxygen to tissues — these modified hemoglobins, or “oxygen therapeutics,” have limited applications. While trauma victims and patients having surgery may one day receive these forms of false blood, no one will exchange all of their own hemoglobin for the store-bought kind.

Another problem with modified hemoglobin is its rapid departure from the body. While transfused red blood cells circulate through the body for months, these blood substitutes leave circulation within a day. PolyHeme and Hemopure are therefore poor substitutes for patients with chronic anemia or chronic blood disorders. For now, these patients will have to continue receiving transfusions of human blood from blood banks.

What effect will Hemopure and Polyheme have on the blood banking industry? Dr. Ness, who is also a consultant for Polyheme’s manufacturer and a former president of the American Association of Blood Banks, anticipates “a fair amount of work” in store for the blood banking industry. For example, doctors will need to be educated about the limited indications of these blood substitutes for patients with chronic blood disorders. If blood substitutes influence the responsibilities of blood banks, Ness points out that the scale of blood banking will not decrease because the need for blood will always be tremendous.

If American doctors start using artificial blood for trauma victims, they will not injure the blood banking industry because artificial blood makers often use real blood to make their product. Northfield Labs, the company that creates Polyheme, buys collected blood too old to transfuse. By removing the membranes of red blood cells, Northfield creates a product that no longer has a blood type. Ness says, “If you calculate the amount of human blood that doesn’t get transfused now, there’s no way that would meet the ultimate need for a blood substitute.” Therefore, blood donations will remain as important as ever if Polyheme enters the market.

Conversely, Biopure uses bovine blood to create its blood substitute, Hemopure. Ness says, “Biopure may alleviate some of the pressure on donors.” This sober statement may lack epic power but it does convey the promises and limitations of current artificial blood products.