Luk Van Parijs recalls exactly when he decided to devote his career to probing the immune system.
Now on MIT’s faculty, he was at the time a Cambridge University undergraduate listening to a lecture on the topic. And what he heard fired his imagination.
It’s probably no surprise, because the immune system is one of nature’s true marvels. With its ability to recognize and destroy everything from pneumonia-causing germs to cancer-ravaged cells, the system helps us ward off the myriad dangers our bodies face daily. It’s also strikingly intricate � as shown by the fact, first detailed by MIT’s Susumu Tonegawa, that the body can fine-tune certain immune cell types to create an almost unimaginable degree of diversity. The result is that there are at least a few cells specifically primed to attack each of the thousands of different infection-causing agents we could encounter in a lifetime before we’re even infected.
“This is an incredibly complicated system,” says Van Parijs, an assistant professor in MIT’s Center for Cancer Research. “There’s an elegance to it, and there’s undoubtedly some sort of logic, too, though we don’t fully understand what it is yet.”
But the system can also go awry and start attacking healthy tissues. Rheumatoid arthritis, juvenile diabetes, lupus, and some forms of leukemia are among many ailments that almost surely result from such “friendly fire.” A new technique for slowing and even halting such attacks, though, promises eventual inroads against these so-called autoimmune conditions, along with cancer and many other ailments.
In a striking display of that potential, Van Parijs recently explored whether he could “silence” genes linked to juvenile diabetes, the inherited form of this common ailment. In experiments with lab rodents bred to be at high risk for the disease, he found that silencing selected genes may in fact help prevent it. His target was an immune-system cell called the killer T-cell. We all have millions of such cells, and despite their ominous-sounding nickname we literally couldn’t live without their infection-fighting prowess. But in juvenile diabetes, killer T-cells run amok.
“They think something’s wrong with the pancreas,” says Van Parijs, , “and they start blowing up the cells that produce insulin.” Using the new technique, Van Parijs’ group all-but shut down the killer T-cells in some mice while leaving others untreated. “Usually, between 70 and 90 percent of this strain of mice develops diabetes,” he says. “In our two groups, most of the control animals got the disease and none of the manipulated ones did.”
Van Parijs emphasizes that the technique is still untested as a therapy. But his findings, with those of others, suggest the emerging approach merits the stir it has created among biologists.
At the heart of the new approach is a natural agent called short-interfering RNA. SiRNAs are snippets of genetic material that occur naturally in plants and animals, and may well be present in our bodies, too.
Experiments have shown that the agent can silence genes. “If you introduce the right kind of siRNA into a cell,” notes Van Parijs, “you can basically shut down or dampen any gene you want.”
That means siRNA may someday be used to combat not only autoimmune conditions but other ailments, including cancer and serious infections. In fact, MIT’s Phillip Sharp, head of the McGovern Institute for Brain Research, has reported that the agent can dampen genes that let the AIDS virus reproduce, in the process cutting the virus’s replication rate far below normal levels.
BELGIUM TO BOSTON
Van Parijs’ work with what may be the new century’s hottest biological phenomenon marks the latest turn in a journey with both intellectual and geographic dimensions.
He finished his pre-college education in his native Belgium. (Van Parijs attributes his ability to speak flawless English to having watched “bad American television � a lot of soap operas.”) He then went to Cambridge, where he became fascinated by the immune system. From there, he moved on to graduate work at Harvard.
“One frustration during that time is that we were succeeding in eliminating cells involved in autoimmune disease or in turning them off, but we didn’t know what was going on inside the cells,” he recalls.
To explore that topic, Van Parijs moved down Massachusetts Avenue to study with David Baltimore, then a famed MIT biologist and a specialist in the types of viruses that can convey most any type of genetic material you want to into cells. Within a week, though, Baltimore was named president of Caltech.
“That first year I saw him twice, perhaps, but I got to know him through a lot of conference calls,” says Van Parijs. Eventually, the investigator himself moved to Caltech, where with the aid of other top young researchers he learned how to use bioengineered viruses to introduce agents like siRNA into targeted cells � an ability that’s key to siRNA’s future as a therapy, because if you can’t get something to ferry your gene-manipulating molecule into a cell, you can’t readily affect that cell’s genes.
Overcoming these and other hurdles means siRNA may remain mostly a research tool for now. But Van Parijs feels siRNA’s ability to let you target several different genes at once will ultimately have medical payoffs.
“In many human diseases with a genetic component,” he says, , “you’re likely to find that there are seven, eight, nine genes involved. If you can silence some, and upregulate others, it could really make a difference.”