For Robert Sah, it's the remarkably practical: to engineer biological replacement joints.

Robert Sah, an HHMI professor at the University of California, San Diego (UCSD), wants to create whole replacement joints—bone, cartilage, and all—outside the body that can then be surgically implanted into patients with osteoarthritis.

The vastness of the problem is one of the things that appeals to Sah, who runs the UCSD cartilage tissue engineering laboratory. “Theories of many materials and systems are very simple and predictable in terms of the phenomenon underlying them—one electrical circuit component can be made almost the same as the next,” he says. “In biology, it's orders of magnitude more difficult to [develop] useful quantitative theories.” The engineering approach works well, he says, because engineers disregard the information they don't need. “Engineers reduce a model to its essential components,” he says.

To fashion his biological joints, Sah needs to answer some fundamental scientific questions. “We need to understand the physiology of the joint. How is the joint lubricant made and maintained? How do mechanical forces cause wear and tear or induce biological responses that may be healthy or damaging?” he says. “During the past decades, scientists and engineers have worked on the individual pieces, and now some of us are trying to put them all together.”

Anseth and Sah are engineers by training, and they seek answers to basic scientific questions as a way to solve practical medical problems. But there are scientists looking through the binoculars from the other end, borrowing engineering methods to improve their grasp of fundamental concepts—sometimes along the way they address practical problems, but that's a secondary benefit.

At the University of Washington (UW), HHMI investigator David Baker is fascinated by how the amino acid chains that make up proteins fold into the specific three-dimensional shapes that allow them to function. In nature, proteins always fold into the most thermodynamically stable shape—spontaneously and rapidly—and Baker is trying to mimic the process on computers. He compared his predictions with data from direct methods of structure determination, such as x-ray crystallography. “That was a way of testing our understanding of the process,” he says.

Once passing that way station, “we realized that another, just as stringent, challenge was to design new protein structures by changing the sequences or coming up with new sequences,” he says. “One of the best tests of understanding is building something.”

Baker admits to seeing the practical side of his work. “I'm very interested in creating new enzymes to do useful things, which is pretty much an engineering problem,” he says. For example, one of his students is developing an enzyme that can turn carbon dioxide—CO₂—into sugar, possibly helping to reduce greenhouse gases. Other conceivable applications for new enzymes include proteins that could speed up pharmaceutical manufacturing or other industrial processes. Baker makes the point, though, that while these are problems with eminently practical goals, he's not tackling them for practicality's sake. Instead, he hopes to use the process of building enzymes as a way to learn more about the fundamental principles that govern how they work.

Photo: Fred Greaves / AP, ©HHMI

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