Researchers at the University of Pennsylvania have constructed from scratch a protein that can do what certain proteins in the human body can: carry and deliver oxygen. This may be a useful step in developing artificial blood.
For years, scientists have tried to create components of artificial blood, in the hope that such a medical advance would circumvent problems of donor blood–such as contamination, limited storage, and short supply–and lead to easier and faster blood transfusions on the battlefield and in trauma cases.
Currently, most blood substitutes include modified versions of natural hemoglobin–the key blood component that delivers oxygen from the lungs to the rest of the body. But research continues because some studies have suggested that existing blood substitutes can increase the risk of heart attacks in trauma victims who have received them.
The Penn team has focused on creating proteins from scratch that can carry oxygen and are essentially waterproof–an important feature. If water enters the protein, it creates a form of oxygen that escapes and causes cellular damage.
“I think it’s a notable achievement in protein design,” says Roman Boulatov, an assistant professor of chemistry at the University of Illinois at Urbana-Champaign. “They show it’s possible to engineer a specific reactivity by starting from scratch. It gives you much more control over what you can change.”
Modifying existing proteins doesn’t always result in a predictable response, and often fails. “There’s a problem working with natural proteins in that they’re complex and fragile,” says Christopher Moser, a biochemist at Penn and coauthor of the new study. “We’d like to learn how to make functional proteins that are completely unrelated to natural proteins: that will allow us to continue to build more features.”
The Penn researchers used three amino acids to make a four-helix columned protein structure. They put a smaller structure inside it called a heme, a large flat molecule that is the active part of hemoglobin. Heme has an iron atom in the center of it, which is what oxygen binds to.
The researchers also made the protein structure flexible, so that it can open to receive the oxygen and close again without letting any water in. They did this by linking together the helical columns with loops to restrict their motions. This gave the final structure a candelabra shape.
“What we learned is that we can make dry interiors in very simple proteins,” says lead author P. Leslie Dutton, a professor of biochemistry at Penn. “A lot of enzyme activity is governed by keeping water away from the [interior].” The work is published in the latest issue of Nature.
To use the artificial protein in the human body, the researchers will need to make sure that it can hold on to the oxygen long enough to be useful, work in a cellular environment, and be nontoxic. The protein also must not be identified by the immune system as a contaminant to be flushed out through the kidneys, adds James Collman, a professor of chemistry at Stanford University, who makes synthetic hemes that bind to oxygen.
“It’s important to have blood substrates because there are so many diseases caused by lack of blood flow, including traumatic hemorrhaging, stroke, and heart attack,” says Howard Levy, the chief scientific officer at Sangart, a company that creates an oxygen-delivering agent. “It really is the bread and butter of intensive-care medicine.”
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