Polly Matzinger

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Polly & Annie

Polly Celine Eveline Matzinger (born 21 July 1947) is an iconoclastic scientist who proposed a novel explanation of how the immune system works, called the danger model.

1 Life and work
2 The Danger Model
3 Publications
4 Films
5 External links

[edit] Life and work

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Polly Matzinger took to science from an unusual background career path which included (according to her C.V.) stints as a Playboy Bunny at a Playboy Club in Denver, a bar waitress, a jazz musician, a carpenter, a dog trainer and a Scientologist. In 1974 Polly Matzinger had dropped in and out of college for years and worked at various jobs before ending up waitressing at a bar frequented by faculty from the University of California, at Davis and here she met Professor Robert Schwab, the head of the university's wildlife program who noticed her talent and persuaded her to take to science.

In one of her first publications, she coauthored a paper with Galadriel Mirkwood for the Journal of Experimental Medicine[1]. It was later revealed that Mirkwood was her Afghan Hound which according to her was as much involved in research as many other coauthors. Matzinger says that papers on which she was a major author were then barred from the journal "until the editor died". When travelling for scientific talks, she sometimes dyes her hair green for the occasion. Although no dogs have been coauthors of any of her recent papers, she is an avid sheepdog trainer, and, with her two Border Collies, Charlie and Lily, was on the team that represented the United States at the 2005 World Sheepdog Finals in Tullamore Ireland.

Polly Matzinger is now a section head at the National Institute of Allergy and Infectious Diseases (her lab is called the Ghost Lab) and her Danger Model has become an important reference point for many immunologists and an inspiration to many students of immunology; it has undergone various minor modifications since its birth announcement in 1994, which can be seen in her more recent theoretical writing.

To many she stands as a symbol of the scientific spirit and its openness.

[edit] The Danger Model

The self-non-self model, the predominant model in immunology since the 1950s, began to encounter problems in the late 1980s when immunologists began to recognize that T-cells depend on other cells to pick up and then present the things to which they will respond — and that the T-cell response depends on whether the other cell (known as antigen-presenting cells) is sending activation signals to the T-cells. In 1989, Charles Janeway proposed that the old model had reached its end, and argued that the innate immune system was the real gatekeeper of whether the immune system responded or did not respond. He also argued that the innate immune system used ancient pattern-recognition receptors to make these decisions - recognizing a pathogen by its unchanging characteristics.

In a 1994 article entitled "Tolerance, Danger and the Extended Family", Matzinger went several steps further by laying out the idea that antigen-presenting cells respond to "danger signals" - most notably from cells undergoing injury, or stress or "bad cell death" (as opposed to apoptosis, controlled cell death). The alarm signals released by these cells let the immune system know that there is a problem requiring an immune response. She argued that T-cells and the immune response they orchestrate does not occur because of a neonatal definition of "self", as in the previous model, nor because of ancient definitions of pathogens, as in Janeway's argument, but on a dynamic and constantly-updated response to danger as defined by cellular damage.

The Danger Model is quite broad, covering topics as diverse as transplantation, maternal/fetal immunity, autoimmunity, cancer treatments, and vaccines, but Matzinger points out that although it offers an explanation of how an immune response is triggered and how it ends, it does not (yet) offer an explanation of why the immune system responds in different ways to different situations. She hypothesizes that tissues send signals to the immune system that determine the immune response appropriate for that tissue, and her lab is now working on experiments to test that hypothesis.

The Danger Model has not won universal acceptance. Some immunologists, following Janeway's ideas more directly, believe that the immune response is mainly fuelled by innate evolutionarily-conserved "pattern recognition receptors" expressed by pathogens such as bacteria, and do not see cell death in the absence of pathogens as a primary driver of immune response. These ideas however, do not explain how the immune system rejects transplants (most well-done transplants are not covered in bacteria), or tumors, or induce autoimmune diseases.

Recently Seong and Matzinger have suggested that the "patterns" that the immune system recognizes on bacteria are not as different from the alarm signals released by damaged cells as one might have thought. They suggested that, because life evolved in water, the hydrophobic portions (Hyppos) of molecules are normally hidden in the internal parts of molecules or other structures (like membranes) and that the sudden exposure of a Hyppo is a sure sign that some injury or damage has occurred. They suggested that these are the most ancient alarm signals, that they are recognized by evolutionarily ancient systems of repair and remodeling, and that the modern immune system piggy-backed on this ancient system. Thus bacteria and other organisms may have very similar alarm systems.

There is now a growing body of work on "regulatory T-cells" which argues that immune activity is stopped by a special subset of T-cells. These ideas challenge several of the key specifics of Matzinger's model. And a student sitting in an immunology class today will likely hear many phrases coined by Matzinger (like "professional antigen-presenting-cell" or "danger signal") but will often hear them in the framework of a self-non-self explanation of immunity.

It takes a long time for an old model to die. Indeed, in an era of increasingly detailed molecular work, many immunologists simply avoid constructing an alternative broad theory of immune function. In that sense, Matzinger has both had to defend her larger theory, and also has had to defend the value of grand theory itself.

[edit] Publications

Matzinger, P. and Mirkwood, G. (1978). In a fully H-2 incompatible chimera, T cells of donor origin can respond to minor histocompatibility antigens in association with either donor or host H-2 type. Journal of Experimental Medicine, 148, 84-92.
Lassila, O., Vainio, O. and Matzinger, P. (1988). Can B cells turn on virgin T cells? Nature, 334, 253-255. (the article in which "professional antigen presenting cells" were first named)
Fuchs, E., and Matzinger, P. B. (1992). Cells turn off virgin but not memory T cells. Science, 258, 1156-1159.
Matzinger, P. (1994). Tolerance, Danger, and the Extended Family. Ann. Reviews of Immunology, 12, 991-1045.
Epstein, M. M., DiRosa, F., Jankovic, D., Sher, A., and Matzinger, P. (1995). Successful T cell priming in B cell deficient mice. Journal of Experimental Medicine, 182, 915-922.
Di Rosa, F. and Matzinger, P. (1996). Long lasting CD8 T cell memory in the absence of CD4 T cells or B cells. Journal of Experimental Medicine, 183, 2153-2163.
Ridge, J.P., Fuchs, E., and Matzinger, P. (1996). Neonatal tolerance revisited: turning on newborn T cells with dendritic cells. Science, 271, 1723-1726.
Ridge, J.P., Di Rosa, F. and Matzinger, P. (1998). A conditioned dendritic cell can be a temporal bridge between a CD4+ T-helper and a T- killer cell. Nature, 393, 474-478.
Gallucci, S., Lolkema, M. and Matzinger, P. (1999). Natural adjuvants: Endogenous activators of dendritic cells. Nature Medicine, 5, 1249-1255.
Matzinger P. (2002). The Danger Model: A Renewed Sense of Self. Science, 296, 301-305.
Seong, S. and Matzinger, P. (2004). Hydrophobicity, an ancient Damage-associated Molecular Pattern that initiates Innate Immune Responses. Nature Rev. Imm., 4, 469-78.

[edit] Films

Immunity: the inside story. Matzinger P and André Trauneker (1986) (video, 13 min) Award winning animated film for lay people describing the events involved in clearing an influenza infection. Translated into German, French, Spanish. Hoffman La Roche studio, Basel, Switzerland

A quick look at tissue rejection. Matzinger P. (1991) (Video, 2 min) Animated Film for lay people describing the events that result in rejection of a skin graft. Commisioned by the National Association of Science Writers for a meeting of television producers. NIH special events department and Capitol Studios

Death By Design. Peter Friedman (1995) (Film, 73 minutes) Award winning Film on apoptotic cell death that features the work of six scientists. P Matzinger, R Levy-Montalcini, M Raff, P Golstein, KM Debatin, R Horowitz

Turned on by Danger. Michael Mosley (1997) (Film, 60 minutes) a ‘Horizon’ program made for public television featuring and delineating the Danger model. British Broadcasting Corporation

Microbe Invasion. David Green (2001) (Film 60 minutes) a program describing the interrelationship between human bodies and the multitude of organisms that live on and within them. The film features the Danger model as the model of immunity that best allows for symbiotic relationships within the body. The Learning Channel