Random Walk
Throop Hall was demolished after the San Fernando earthquake, and the Calder Arches now adorn the facade of the Arnold and Mabel Beckman Laboratory of Chemical Synthesis. The Throop site is now a vest-pocket park in the middle of campus—a perfect place for a photo op. Here Lemelson winner Heather Agnew (right) and finalist Yvonne Chen enjoy their accolades
Lemelson Winners Announced
Deep in the Amazon, a woman is keeling over with stomach pains and vomiting. Does she just have the flu, or is she one of two billion people worldwide who has been afflicted with Hepatitis B, a potentially deadly liver disease? Today’s diagnostic tools are too delicate for health workers to use in the steamy environment of a remote jungle. But in the future, a drop of blood from a prick of the finger and a cheap, simple device that works in nearly all conditions may change that. Heather Agnew (PhD ’10) and Jim Heath, the Gilloon Professor and professor of chemistry, are working to make such devices a reality. For her role in this effort, Agnew has won the $30,000 2010 Lemelson-MIT Caltech Student Prize.
A diagnostic test, or assay, can measure the amount of a protein specific to some disease by allowing it to bind to another molecule, called an antibody, that is tailor-made to recognize it. Assays can be packaged into easy-to-use kits for diagnosis outside the lab, and they’re not restricted to blood. For example, the home pregnancy test assays a hormone called human chorionic gonadotropin in urine.
The problem with such assays, though, is that the antibodies themselves are proteins, sensitive to heat, humidity, and other factors. For instance, HIV assays have to be performed within hours of opening the package or the antibodies degrade, Agnew says. But the developing world, which needs such simple diagnostic tools the most, isn’t always air-conditioned. Furthermore, antibodies are expensive to produce. Today, many tests look for just one or two proteins, Agnew says. But diseases like cancer are complex, so an accurate diagnosis might require the measurement of more than a dozen proteins, each by its own antibody.
Agnew and her colleagues are building cheap, durable antibody replacements called protein-capture agents out of synthetic peptides, which are relatively short chains of amino acids—the building blocks of proteins. Peptides are cheap to make, and can be designed to have all sorts of nice properties, including heat resistance and biological or chemical stability. But since they’re small molecules, they don’t stick to their target proteins as well as antibodies do.
Reasoning that two peptides of middling stickiness might do the trick if they worked together, Agnew and her coworkers tested millions of them. And here the project got help from the target protein itself—when appropriately primed versions of the peptides recognized the protein and bound to it, it held them in just the right orientations that they could “click” together to create a new molecule that is 10 to 100 times better at binding to the target protein than either peptide alone. Repeating the process to add a third peptide further enhances the binding.
As for durability, Heath’s benchmark is what he calls the Pasadena Test: will it work even after a year spent baking in the trunk of his car? Agnew says her protein-capture agents have withstood airplane travel and years of sitting on a shelf in her office.
A second award of $10,000 went to Yvonne Chen (MS ’07), a grad student working with Christina Smolke, a former assistant professor of chemical engineering at Caltech who’s now at Stanford. Chen developed a way to help T cells fight cancer. T cells are a part of the body’s protective army, and other researchers have been able to engineer them to attack cancerous tumors. “We can keep putting them in the blood supply until they home in on the tumor,” Chen explains. “The problem is that they die really quickly.” Because T cells are a part of the body’s natural immune response, they die by default if they aren’t instructed to attack. “Our challenge then is to figure out how to engineer this T-cell population to be sustainable so they can finish killing the tumor cells.”
T cells are kept alive by molecules called cytokines. But you can’t just inject cytokines into someone to keep the T cells going—you’d need a lot, and too much would put the patient into shock. One solution is to engineer the T cell to produce its own cytokines. But you also have to regulate cytokine production carefully, because an excess will cause the T cells to reproduce nonstop, resulting in leukemia.
With Smolke, Michael Jensen from City of Hope medical center, and other researchers, Chen made a molecule of RNA—which is similar to DNA—that acts like a switch, turning cytokine production on when exposed to theophylline, a caffeine-like molecule (see E&S 2005, No. 4). When the theophylline infusion stops, so does cytokine production, and the T cell dies. This is just a demo, as large doses of theophylline can cause an irregular heartbeat and even death. Fortunately, the RNA switch can easily be designed so that it responds to a harmless molecule, such as a vitamin. Chen is now working to make it more versatile and easier to control.
The Lemelson-MIT Caltech Prize is funded by the Lemelson-MIT Program, founded in 1994 by Jerome H. Lemelson to inspire young innovators. Chen’s prize as a finalist was donated by Michael Hunkapiller (PhD ’74). Lemelson-MIT student prizes are also at MIT, Rensselaer Polytechnic Institute, and the University of Illinois at Urbana Champaign. The Caltech prize was first awarded last year. —MW
