University of Minnesota
December 23, 2008
Researcher Christy Haynes constructs an immune system, one cell at a time
By Deane Morrison
It's said that no one understood how birds could fly until the airplane was invented. Now, University of Minnesota researcher Christy Haynes is applying the same tactic to understanding the human immune system: She's building one.
Although much is known about asthma and allergies, clues to controlling or curing these conditions still lie hidden in the maze of immune cell interactions. As she builds "an immune system on a chip," Haynes will isolate and study the various way cells communicate and respond to each other, with the goal of opening new avenues for treating allergic reactions and asthma.
Her idea has garnered funding from a very selective source. This fall Haynes, an assistant professor of chemistry, became one of 31 researchers tapped by the National Institutes of Health for a New Innovator Award, worth $1.5 million over five years.
The awards embody NIH's investment in fresh approaches "that could transform biomedical and behavioral science." Now in its second year, the program supports a total of 61 investigators nationwide.
"I think they were looking for a 'blue sky' proposal," says Haynes. "This is a big deal for my group. [This research] couldn't happen without this money."
We know what you're thinking: What's a chemist doing studying the immune system? It all goes back to Haynes's previous work with nanoparticles, pieces of matter whose minuscule size—less than 100 billionths of a meter—gives them unusual properties. Haynes was studying how nanoparticles of gold change color under certain chemical conditions.
"Then we started asking, 'You can buy all these products like sunscreen with nanoparticles. What happens when they get into the body?'" she says.
Soon Haynes was delving into the toxicity of nanoparticles. She applied gold nanoparticles to mast cells, which release histamine (a chemical that helps cause inflammation, congestion, narrowed airways and other miseries) during an allergic response. The mast cells responded to the nanoparticles by releasing more histamine—and faster. Haynes became intrigued with the immune response and how one could do a better job treating disorders like hay fever and asthma.
"When we treat immune disorders, we almost always treat the symptoms, such as by using anti-histamine," she notes.
Like many other bodily functions, the immune system works through messages in the form of chemicals passed between different cell types. These messages often cause the recipient cell to react in some way, such as by releasing another chemical. To help Haynes see the system in action, staff of the University's Nanofabrication Center have built flexible plastic "chips" the size of a credit card, each holding tiny wells connected by canals.
"When we treat immune disorders, we almost always treat the symptoms, such as by using anti-histamine."
To start, Haynes will culture just one type of cell in one well and characterize its behavior. Gradually she will add more cells and let them interact by producing and sending chemical messages through the canals.
First up will be mast cells. After manufacturing histamine, the cells store it below their outer membranes in packets called granules. The histamine only makes its mischief when the granules are released in response to a signal.
To see how that happens, consider a person with an allergy to ragweed pollen. The lining of their nasal passages contains mast cells, the outer membranes of which are coated with antibodies called IgE. Each IgE molecule is held in place by a mast cell structure called an IgE receptor. Produced and secreted by white blood cells, the IgE is specifically designed to stick to ragweed pollen and nothing else.
When the person inhales the pollen, the IgE molecules grab it. This signals the mast cells to release their histamine, and the sneezing begins. But since ragweed pollen is otherwise harmless, the whole thing amounts to a false alarm. What no one knows, says Haynes, is whether the process can snowball. That is, could a person's mast cells, when exposed over time to increasing amounts of IgE, build more IgE receptors? And if so, would this increase the response—i.e., more histamine—and make allergies worse?
To find out, Haynes will expose mast cells to rising amounts of IgE and measure how much histamine they release [see sidebar]. Later, she will put white blood cells that make IgE in another well and let them communicate with the mast cells. In these and other experiments, she will monitor the fluid in the canals to see exactly what chemical messages are being sent and correlate them with cells' behavior.
How to count molecules
To count molecules of histamine released by mast cells, Haynes uses a technique in which a tiny electrode is placed right over the cells. As histamine molecules are released, the electrode attracts electrons away from them. The movement of electrons produces an electric current whose intensity reveals how much histamine has been released.
Collaborating with Haynes is James White, a Regents Professor of laboratory medicine and pathology. He will supply samples of platelets, including some from patients with immune-related disorders. Although not technically cells, platelets may play a role in the inflammation that occurs in some allergic responses by interacting with white blood cells and chemical messengers. As she embarks on the research, Haynes is keeping an open mind about what she may find. But one thing's for sure.
"We're going to be the people who tell you what's not working in cells," she says. "Some [researchers] have ideas about targets [for therapy] and candidate drugs. [We'll be able to] see how they work and if the drugs do what they are supposed to."
Department of Chemistry