Polly Matzinger followed a rather unusual path into science.
Her ‘Danger model’ reshaped our understanding of the human immune system after she rejected the accepted self/non-self model. The self/non-self model said that the immune system attacks ‘non-self’ cells, but ignores cells it sees as rightful parts of our bodies – ‘self’ cells.
Polly Matzinger proposed that our immune systems are actually activated by the products of cell damage or unexpected cell death. In other words, her theory is that our immune systems are activated when our cells signal “we are being harmed, there is danger.”
Beginnings
Polly Celine Eveline Matzinger was born on July 21, 1947 in La Seyne, close to the French Mediterranean city of Toulon.
Her mother, Simone, was French; a former nun, she had become a potter.
Polly’s father, Hans, was Dutch. He had survived Dachau concentration camp where the Nazis imprisoned him in 1944 for the ‘crime’ of aiding Jews. Hans was an artist; he also worked as a carpenter to provide his family with a steady income.
No Chance of Success
The Matzingers arrived in New York in 1954. Finding their daughters Polly and Marjolaine barred from Long Island’s public schools because they spoke no English, the family moved to Hollywood, California, where two more sons were born: Tangy and Jeal.
At age 11, Polly began a lifelong love affair with dogs and dog training when she took Trixie the beagle to a training class.
The Matzingers relocated several times in California. Polly, who often felt isolated, finished high school described in her senior-class yearbook as:
A Dog Whisperer with a Loathing of Boredom
In 1965, age 18, Polly Matzinger started a B.S. at the University of California, Irvine. The classes bored her; her enthusiasm waned.
Years later, she had still not graduated. She cleaned bricks, cleaned shirts, trained problem dogs, trained people to train problem dogs, played jazz bass in bars, and – her best earning job of all – worked as a Playboy bunny in Boulder, Colorado.
She felt that sooner or later most jobs grew stale. She decided to work permanently as a cocktail waitress, leaving her free during the day to do the important and interesting things in life – composing and playing music, working with animals and reading.
She was determined to live a creative life and escape boredom.
The Case of the Inquisitive Waitress
In 1972, age 25, Matzinger was working in Mrs B’s bar in Davis, California. Two of the regulars were biology professors. With her interest in animal behavior – particularly dog behavior – she enjoyed listening to them talking shop over their beers.
One day the professors began talking about mimicry in the animal kingdom, such as how a hoverfly dresses itself as a wasp to deter predators. Suddenly their waitress posed questions they couldn’t answer.
Hoverflies have no stings. They increase their chances of survival by mimicking wasps.
Why, she asked, didn’t any animals mimic the skunk? For example, why are there no black and white striped raccoons? Intrigued, Professor Robert Schwab started having regular conversations with Matzinger about science. He told her that her questioning mind was the mind of a true scientist. He brought science articles into the bar for her to read and encouraged her to study biology.
If she became a biologist, he insisted her work would never bore her.
Was it Horror or Delight?
In 1974, nine years after she first matriculated, Matzinger returned to the University of California, Irvine. In 1976, she completed her B.S. in biology.
She moved to the University of California, San Diego and completed a PhD in biology in 1979. She was now 32 years old.
She was 10 years older when she returned to America after spells at the University of Cambridge and the Basel Institute for Immunology. She returned as Section Head at NIAID – the U.S. National Institute of Allergy and Infectious Diseases.
A Shaggy Dog Story!
In 1978, Matzinger submitted a paper to the Journal of Experimental Immunology. She couldn’t bear writing the whole paper in the customary scientific third person, “it was believed… it was shown… it was decided… etc.” She decided instead to write, “we believed… we showed… we decided…”
The trouble was the work was all her own, but she didn’t want to write, “I believed… I showed… I decided…”
So, she enlisted her dog, an afghan hound by the name of Galadriel Mirkwood, as co-author. The paper, authored by Matzinger and Mirkwood, was accepted and published.
Soon enough the journal’s editor discovered Galadriel Mirkwood’s lineage was canine rather than human. The Journal of Experimental Immunology refused to publish any more of Matzinger’s work until the editor’s death over a decade later.
The Danger Model of the Immune System
In 1994, Matzinger introduced the Danger model – a new explanation of how the human immune system works.
The new model proved divisive – some distinguished professors in the field recoiled in horror, while others, perhaps younger and less distinguished, beamed with approval.
Self and Non-self: The Previous Theory
In the 1940s, Macfarlane Burnet was obsessed with the immune system. He said that to explain how it worked, scientists needed to figure out how our bodies distinguish between our own cells and invading cells – in other words between self and non-self.
In 1949, Burnet proposed our bodies learn this in the womb. Any cell types a fetus encounters are taken to be self. The cell types a fetus does not encounter are taken, after birth, to be invaders and will provoke a response from our immune systems. In 1956, Peter Medawar’s team confirmed Burnet’s prediction with experiments on mice.
Skin grafts from one mouse to another usually fail because the graft is rejected by the mouse receiving it. However, the situation changes if a mouse fetus is exposed to cells from a donor mouse. When the fetus grows into an adult, it will accept skin grafts from the donor mouse. In other words, it is possible for foreign cells to be treated as ‘self.’
In 1960, Burnet and Medawar shared the Nobel Prize in Physiology or Medicine for their work.
BUT
Problems began to emerge with the self/non-self model. To solve these problems scientists began adding more cells and immune signals to the model. This work was especially important to Ephraim Fuchs, who worked with Matzinger at NIAID. He had become a medical researcher after two close family members died from cancer.
Building the Danger Model
Fuchs and Matzinger talked a lot about the immune system. In one of these conversations, Fuchs suggested they consider how an immune system would evolve by natural selection: an immune system that evolved to fight only dangerous intruders would be far more efficient than one that fights everything that’s non-self.
Matzinger began to think. Burnet had said the immune system was explained by its responses to self and non-self. Yet, in addition to failing to explain the lack of response to tumors, the self/non-self model also failed to explain the lack of a response from a mother to a fetus developing in her womb, and failed to explain why we have gut bacteria that are not attacked, etc.
Perhaps, she thought, the immune system was somehow distinguishing between harmless and dangerous.
Unnatural Death
After months of reading and contemplation Matzinger experienced a moment of revelation. She recalled that cells in our bodies die in two different ways:
- natural, programmed death – cells shrivel up and do not release their insides
- unnatural death – cells burst open, spilling out their contents
Could it be that our bodies detect cells spilling out their contents, and this activates a response form the immune system?
In their early stages, cancers are simply groups of cells growing very quickly. They don’t cause our own cells to burst open, so they don’t produce a danger signal and our bodies ignore them until it is too late.
Transplants can fail not because of a self/non-self issue, but because the damage suffered by the cells in the tissue being transplanted results in a danger signal, producing an immune system response.
Completing the Danger Model
Matzinger completed her initial Danger model when she realized there is a type of cell in the body ideally suited to the role of noticing and signaling the un-programmed death of cells – the dendritic cell.
Her model looked even better when she learned that in the 1970s, another researcher, Kevin Lafferty, had discovered:
- that dendritic cells are killed by oxygen
- he could transplant thyroid glands between animals without provoking an immune response provided the glands were treated with oxygen, killing the dendritic cells – the very cells which Matzinger now suspected provoked a response from the immune system by signaling the un-programmed death of cells.
Unfortunately, Lafferty’s work was disregarded when he published it.
Matzinger published her theory in the Annual Review of Immunology in 1994 with the title Tolerance, Danger, and the Extended Family. It was quickly picked up by science magazines and newspapers.
“Mel Cohen says that the scientist who’s willing to stick his neck out and be clear will contribute to the field whether he or she is wrong or not; because if they’re wrong, somebody will do the experiments to prove they’re wrong and in the process learn something about Nature. So whether I’m wrong or right doesn’t matter. What matters is that it’s clear and we’re going out and saying it.”
The Danger Model Today
The danger model has, in part, become accepted science. However, no single model has been found that fully explains the immune system. Indeed, the system may be multi-faceted – it may not be explicable in terms of any single model.
Some Personal Details
Polly Matzinger is not married and has no children. Her dogs are her family. She is head of the T-Cell Tolerance and Memory Section at the National Institute of Allergy and Infectious Diseases.
Author of this page: The Doc
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Thanks
Image of Polly Matzinger courtesy of Ontario HIV Treatment Network
Further Information
Turned on by Danger
BBC Horizon Documentary, 1997
Ted Anton
Bold Science
W. H. Freeman & Company, 2001