Boosting Immunity

Young engineers are often more excited about solving technical problems than meeting immediate needs; consequently, they end up creating new devices or materials without knowing where and how they might be useful. But early in his career, materials scientist Darrell Irvine, PhD ‘00, decided that he didn’t want to find himself in that position. Instead, he immersed himself in immunology, a complex and exciting field where materials science hadn’t been applied much, and began building solutions to its particular problems. “It seemed it was an area where you could intervene with smart materials,” Irvine says.

Irvine began his work in immunology at Stanford University, where he spent almost two years as a postdoc. Walking in with minimal knowledge of immunology was “mostly frightening,” he says. But he didn’t let that deter him. He spent long hours in the lab, essentially taking a crash course in immu­nology, before coming back to MIT in 2002 to start his own lab as an assistant professor of biomedical engineering. One of his main projects now is designing and testing tiny particles of synthetic material as a way to package and deliver vaccines. He hopes that this new kind of packaging will help vaccines stimulate stronger and more effective immune responses, while avoiding some common side effects such as inflammation, fever, and shock.

Although other researchers have worked on combining biomaterials with vaccines, Mark Saltzman, SM ‘84, PhD ‘87, a chemical- and biomedical-engineering professor at Yale University, says Irvine is different. “People like Darrell have decided that they need to have a high level of sophistication in both areas of science to really make progress,” he says. Indeed, Irvine believes that his time at Stanford elevated the quality of his research. Instead of making technology that will work for something somewhere someday, he will try to apply his skills to particular problems in the hope that he can enhance the basic understanding of immunity.

Cell Commandos
On a computer monitor, Irvine plays a time-lapse, black-and-white video of mouse immune cells in a lab dish interacting with one of his synthetic materials. The video, at 40-times magnification, shows dozens of immune cells, called dendritic cells, swarming around a single microparticle. Like football players jumping on a fumbled ball, the cells pile on top of the microparticle until it almost disappears.

In the video, the microparticle is simulating the body’s response to an invading pathogen, such as a virus. When a virus enters the body, it stimulates the cells near the site of infection to release specific immune-signaling molecules. These molecules in turn call in the dendritic cells. Acting like a reconnaissance team, the dendritic cells arrive at the infection site and absorb samples of the virus. They then carry their samples to the lymph nodes, to instruct other immune cells to hunt down and destroy the rest of the virus population.

Viruses initiate strong immune responses, but new vaccines under development do not. This could be one reason why they have often been ineffective, providing little protection against future infection.

Irvine says vaccines that use biomaterials could succeed where their predecessors have failed. His microparticle, about 10 to 20 micrometers in diameter and made of a biodegradable polymer used in other medical devices, carries and slowly releases the immune-signaling molecules that attract dendritic cells. Vaccines under development haven’t been very good at rallying these cells. Irvine’s team has already shown that the microparticles work in lab dishes and is now working to prove that they will elicit the same response in mice.

But the migration of dendritic cells is only the first step in the immune response. The cells also need to collect samples of the virus and call in reinforcements. For this step, Irvine has created other, much smaller particles. These nanoparticles, roughly .5 micrometers to one micrometer in diameter, carry with them two different types of molecules: one instructs the dendritic cells to head for the lymph nodes, and another identifies the pathogen the immune system must seek.

Ultimately, Irvine believes, the two types of particles could work together in a vaccine. The microparticles would attract the dendritic cells, and the nanoparticles would give them their marching orders. Irvine and his team are now trying to bind the nanoparticles to the surface of the larger microparticle, so that they can work in concert.

Equipping Vaccinologists
Immunology is a field begging for expertise of the sort Irvine brings. For many years, researchers have struggled to develop vaccines against some of the world’s most deadly diseases, and they’re growing desperate for new strategies and technologies. “The old ways of making vaccines don’t work for all of the horrible worldwide infectious diseases like HIV, tuberculosis, and malaria,” says Norman Letvin, a professor of medicine at Beth Israel Deaconess Medical Center in Boston. “The easy vaccines”—such as the polio and smallpox vaccines—”have been made, but the difficult ones are really difficult,” says Letvin, who is trying out some of Irvine’s materials as part of his work on an HIV vaccine.

Vaccine makers know that it’s important to vaccinate people using several different immune system-stimulating molecules. But they think their new vaccines have been failing because they haven’t been able to control where or how fast those molecules spread through the body or how quickly enzymes chew them up, decommissioning them before they’ve had a chance to do their work.

“We need to control the degradation, release, and localization” of the vaccine, says Letvin. “Biomaterials are potentially a powerful tool for this.” By encapsulating or binding key vaccine ingredients with biomaterials, Irvine hopes to give vaccinologists the control they seek. The result could be vaccines that stimulate precisely the right immune response without causing side effects.

Irvine will, of course, need to deal with the same safety issues all vaccinologists face. The immune system is powerful, and manipulating it in the wrong way could have disastrous consequences. Because Irvine’s technology involves the fundamental biological mechanisms of the immune system, “the potential benefits are huge. But the potential risks become bigger as well,” says Yale’s Saltzman.

But regardless of whether his novel materials prove useful in the short term, Irvine is breaking new ground by bringing engineering principles and quantitative analysis to immunology. “He’s showing us that you can understand complicated biology and design materials,” says Saltzman. “He’s showing you can do both things at once.”