九华山三日游攻略:A CONVERSATION WITH POLLY MATZINGER

r. Polly Matzinger, 50, a tenured medical researcher at the National Institutes of Health, is turning the world of immunology upside down with her radical theory suggesting that the human immune system is activated not by alien substances in the body, but by dangerous ones -- the Danger Theory of immunology. She sat in her Bethesda, Md., garden recently, explaining the evolution of her ideas. 

DR. MATZINGER. A jockey, a seeing-eye dog trainer, a composer. I grew up in a very creative original family. My mother, a French ex-nun, is a potter. My father, a Dutch World War II resistance fighter who was imprisoned in Dachau, is a painter and carpenter. My sister is an artist and my brother is a mechanic and rock musician.

I sing, play piano and bass and compose music. But I don't sing or play very well, and the music I write is dead-boring. The only thing I've found that I'm really creative in ... is science. It wasn't an art form I expected to find, but then, my family has always blazed their own trails.

Q. How did you find science?

A. I was a cocktail waitress in Davis, Calif. in 1972. I'd been in and out of school and done all kinds of jobs -- jazz musician, lab technician, problem-dog trainer and Playboy bunny, which was, incidentally, a great job. But everything seemed to get boring after a while, so I decided to make a career of waitressing and save the days for reading, composing and working with animals.

One day, two professors from the University of California at Davis who regularly came in for beer, started talking about animal mimicry, and I asked them, "Why has no animal ever mimicked a skunk?" Professor Robert Swampy Schwab, who was chair of Wildlife and Fisheries, was floored. He decided that this question-asking waitress should become a scientist.

For nine months, he came to the bar and brought me all kinds of scientific articles. And he convinced me that science never gets boring. At his urging, I applied to graduate school. I started in 1974, got a belated bachelor's degree in '76 and a Ph.D. in '79. I owe that man my life.

Q. When did you begin questioning the ideas that are the bedrock of immunological theory?

A. In graduate school, we learned that the immune system fights anything that isn't part of our bodies. But that didn't make sense to me. I wondered why mothers didn't reject their fetuses, why we didn't reject the food we eat, or the stuff in the air we breathe. But my professors all said, "Don't worry about it."

So I stopped worrying. This is a cowardly habit that we scientists can fall into. If we really can't answer a question, we sometimes stop asking it. Ten years later, I came to the National Institutes of Health and met a brilliant young oncologist, Ephraim Fuchs. He wondered about these questions, too. And we began thrashing them out.

Q. How does your Danger Model differ from the standard Self/Nonself Model of the immune system?

A. It isn't really insurrectionary -- it's just a different way of looking at things. Let me use an analogy to explain it. Imagine a community in which the police accept anyone they met during elementary school and kill any new migrant. That's the Self/Nonself Model.

In the Danger Model, tourists and immigrants are accepted, until they start breaking windows. Only then do the police move to eliminate them. In fact, it doesn't matter if the window breaker is a foreigner or a member of the community. That kind of mutant behavior is considered unacceptable, and the destructive individual is removed.

The community police are the white blood cells of the immune system. The Self/Nonself Model says that they kill anything that enters the body after an early training period in which "self" is learned.

In the Danger Model, the police wander around, waiting for an alarm signaling that something is doing damage. If an immigrant enters without doing damage, the white cells simply continue to wander, and after a while, the harmless immigrant becomes part of the community.

Q. How did you arrive at your alternate model for the immune system?

A. It didn't happen in a day. There were two difficult parts. First Ephraim and I took a year to realize that a truly useful immune system would fight dangerous things and ignore harmless ones. But we couldn't figure out how to tell the difference. One day, while I was in the bath, the answer just popped out! It was: "Things that are dangerous do damage. No damage, no danger." It seems really simple, doesn't it? But it took us a long time.

Next we had to figure out how the white blood cells learn about the damage. That thought also arrived oddly. Annie, my Border collie, and I were watching over some sheep grazing in a field. Suddenly something moved in the woods, startling the sheep, and Annie jumped up to protect them. It hit me that something was amiss. Well, almost every organ of the body has a few sentinels -- called dendritic cells -- that are like sleeping sheep dogs. Alarm signals from injured cells could wake them up and alert the immune system.

Q. What is the value of your theory of the immune system?

A. Besides the beauty of it? Well, first, it explains many things the old model couldn't -- like why mothers don't reject their fetuses. They don't do damage. Second, there are some important practical implications. For example, the old model assumed that very young babies would be really hard to vaccinate because their immune systems were busy learning who the "self" was. Then we published a paper showing how to vaccinate 1-day-old baby mice. Now there's a lot more hope about early vaccination.

Another hopeful area is cancer treatment. I really believe we can use vaccination to cure perhaps 80 percent of all cancers. Though there's a lot of research in this area, it isn't working very well. The Danger Model predicts that some simple changes could make anti-cancer vaccinations very effective.

Q. But there is a lot of resistance to making those simple changes, based on your theory, isn't there?

A. The resistance isn't really to the changes. It's to the Danger Model itself. People grew up with a particular view of how immunity works. When I say, "That's not how it works -- please accept that for a moment and you'll see we could do something effective against tumors," they are unable to try. It's partly fair. The Danger Model is new, and to experiment on people, you need to have a sound basis for the treatment. Still, I don't understand why they won't try it on cancer in animals.

Q. What's the next big question in immunity?

A. Once we know what activates it, we next have to learn how to make the right kind of response. Viruses aren't cleared the same way as worms, and right now nobody has a clue how the immune system knows the difference. There's not even a theory. My lab is just starting to move in that direction, and I'm thinking hard about it.

Q. I'm told you dislike the way science and technology have become hyphenated terms -- why?

A. Because they are very different. Science is more like art and true scientists are more like artists. Except that we don't have to starve in garrets because governments and foundations pay us. Technology is about vaccines and plastics and drugs and things that work in the world. Science is about describing nature, and so is art: We're painting nature.

Q. Do you think the scientific world is too solemn?

A. Oh, no. Not true science. It's art. Actually, it's a sandbox and scientists get to play all of our lives