Polly Matzinger

Polly and Annie

Polly Celine Eveline Matzinger (born July 21, 1947 in La Seyne, France) is an immunologist who proposed the danger model theory of how the immune system works.[1]

Early years

Polly Matzinger was born in July 21, 1947 in France, of a French mother (Simone) and a Dutch father (Hans).[1] She immigrated to the US, along with her parents and sister (Marjolaine) in 1954. Before finishing university, she worked at many different kinds of jobs. She was a jazz musician (playing the string bass), a carpenter, a dog trainer, a waitress, and a Playboy Bunny.[2][3] Although it took her eleven years to finish her undergraduate degree, she finished her BS in biology at the University of California, Irvine in 1976.[3] She was talked into going to grad school by Professor Robert Schwab of UC Davis and finished her PhD in Biology at the University of California, San Diego in 1979.[4][5] She then did four years of postdoctoral work at the University of Cambridge[3] and was a scientist at the Basel Institute for Immunology for six years, before heading to the National Institutes of Health in Bethesda, Maryland.[5]

Ghost Lab at NIAID

Polly Matzinger was a section head at the U.S. National Institute of Allergy and Infectious Diseases (NIAID) until April 2013. Matzinger and her coworkers referred to the lab as the "Ghost Lab" when listing their affiliation in papers. The nickname was given to the lab by her colleagues when Matzinger first arrived at the NIH because she spent the first nine months studying a new field (chaos theory) that she thought might apply to the immune system, and the lab sat empty. The formal name of her laboratory was the T-Cell Tolerance and Memory Section of the Laboratory of Cellular and Molecular Immunology.[6] On average, the Ghost Lab hosted three postdoctoral researchers at any one time.[7]

On April 1, 2013, NIAID administration closed the Ghost Lab. The T-Cell Tolerance and Memory Section was incorporated into the Laboratory of Immunogenetics, but without any funding for research, and Matzinger's research was effectively shut down. Since that time she has given a series of eight lectures explaining the function of the immune system from the point of view of the danger model. These lectures were taped and can be found on the NIH videocast website[8]. The lectures cover immunological theory, transplantation, pregnancy, tumors, autoimmunity, T regulatory cells, tissue control of immunological class, allergy, parasites and the nature of danger signals.

Research

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, drawing on the ideas of Thomas Kuhn, Charles Janeway proposed that the old immunological paradigm had reached the limits of its usefulness—or, as he described it, the asymptote of the increase in knowledge which it had brought. Janeway 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.

Danger signals

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, 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 occurs not 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 because of a dynamic and constantly updated response to danger as defined by cellular damage.

Scope

The danger model is broad, covering topics as diverse as transplantation, maternal/fetal immunity, autoimmunity, cancer treatments, and vaccines, but Matzinger points out that the original model was designed to offer an explanation of how an immune response is triggered and how it ends, but did not offer an explanation of why the immune system responds in different ways to different situations. She has now extended the model to hypothesize that tissues not only send signals alerting the immune system to local damage and stress, but that the tissues also determine the immune response appropriate for that tissue. Before her lab was closed, it was working on experiments to test that hypothesis. She is currently seeking collaborations to continue the research.

The danger model has not won universal acceptance. Some immunologists, following Janeway's ideas more directly, believe that the immune response is mainly fueled by innate evolutionarily conserved "pattern recognition receptors" which recognize patterns expressed by microbes such as bacteria, and do not see cell death in the absence of pathogens as a primary driver of immune responses. These ideas however, do not explain how the immune system rejects tumors, induce autoimmune diseases, or generate allergy and asthma.

Pattern recognition and a tissue-driven immune system

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 of molecules are normally hidden in the internal parts of molecules or other structures (like membranes) and that the sudden exposure of a hydrophobic portion 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. They describe these ancient signals as danger-associated molecular patterns, or DAMPs.

In a 2013 article in Nature Immunology, Matzinger makes a case for what she now views as the most important implication of the danger model: that the tissues of the body are a large part of what drive immune response. She argues that immunologists have had overly simplistic and schematic ideas about immune response because of the limits of their assays, and that organs are likely to induce immune responses that are best-suited to defending the organ from the damage of microbes but also from the damage of the immune system itself. She also asserts that the relationship of the immune system to commensal bacteria remains poorly understood but is likely to be important.[9]

Matzinger argues that the idea of DAMPs may explain why Toll-like receptors seem to respond both to external and endogenous signals (while acknowledging controversy over this issue). By emphasizing her theory that the tissues drive the nature of the immune response (i.e., the "what type" rather than the "whether" of immune response), Matzinger describes a dynamic immune system with complex webs of signalling, rather than an immune system that can be explained by a simple and easily reducible set of molecular signals that initiate response or by a small set of cells (e.g., regulatory T cells) that shut it down.

Challenges to Matzinger's theories

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. Matzinger argues that these cells are misinterpreted because their functions have not been explored enough. To date (with rare exceptions) these cells have been tested almost exclusively for their ability to suppress highly inflammatory immune response types. The exceptions are illustrative in that they show that regulatory T cells can also act as helper T cells for immune responses in the gut and mucosal tissue. Matzinger argues that their function is to maintain the right kinds of immune responses in the right places, and that they are controlled by signals from the tissues that they protect.

A student sitting in an immunology class today will likely hear many phrases coined by Matzinger, such as "professional antigen-presenting-cell", "danger signal", or "DAMPs", but will often hear them in the framework of a self/non-self explanation of immunity. Other immunologists have often adapted parts of Matzinger's ideas without adopting the danger model as a theoretical framework. Indeed, in an era of increasingly detailed molecular work, many immunologists simply avoid constructing an alternative broad theory of immune function. One immunologist believes that the immune system is not a single system at all, and is instead a set of mechanisms "cobbled together" by evolution.[10] If this is true, no single theory can explain the function of the system as a whole. For both of these reasons, Matzinger has had to defend her larger theory, but also has had to defend the value of grand theory itself. She argues that, without a theoretical framework on which to hang the data, much will be missed.

The Uiversity of Rhode Island Institute for Immunology and Informatics has named a scholarship for her: the Polly Matzinger Fearless Scientist Scholarship. [11]

Dog co-author controversy

In one of her first publications, a paper for the Journal of Experimental Medicine, she listed a dog as a coauthor.[12] Ted Anton described the decision in his book Bold Science: "Refusing to write in the usual scientific passive voice ('steps were taken') and too insecure to write in the first person ('I took the steps'), she instead invented [a] coauthor": her Afghan Hound, Galadriel Mirkwood.[13] Once the deception was discovered, papers on which she was a major author were barred from the journal until the editor died and was replaced by another.[14]

Publications

  • Matzinger P., 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 (1): 84–92. doi:10.1084/jem.148.1.84. PMC 2184911. PMID 78964.
  • 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., Matzinger P. B. (1992). "B cells turn off virgin but not memory T cells". Science. 258: 1156–1159. doi:10.1126/science.1439825.
  • Matzinger P (1994). "Tolerance, Danger, and the Extended Family". Annual Review of Immunology. 12: 991–1045. doi:10.1146/annurev.iy.12.040194.005015. PMID 8011301.
  • Ridge J.P.; Fuchs E.; Matzinger P. (1996). "Neonatal tolerance revisited: turning on newborn T cells with dendritic cells". Science. 271: 1723–1726. doi:10.1126/science.271.5256.1723.
  • Ridge J.P.; Di Rosa F.; Matzinger P. (1998). "A conditioned dendritic cell can be a temporal bridge between a CD4+ T helper cell and a T- killer cell". Nature. 393: 474–478.
  • Gallucci S.; Lolkema M.; Matzinger P. (1999). "Natural adjuvants: Endogenous activators of dendritic cells". Nature Medicine. 5: 1249–1255. doi:10.1038/15200. PMID 10545990.
  • Matzinger P (2002). "The Danger Model: A Renewed Sense of Self" (PDF). Science. 296: 301–305. doi:10.1126/science.1071059. PMID 11951032.
  • Seong S., Matzinger P. (2004). "Hydrophobicity, an ancient Damage-associated Molecular Pattern that initiates Innate Immune Responses". Nature Reviews Immunology. 4: 469–78. doi:10.1038/nri1372. PMID 15173835.
  • Matzinger P (2007). "Friendly and dangerous signals: is the tissue in control?". Nature Immunology. 8: 11–13. doi:10.1038/ni0107-11. PMID 17179963.
  • Matzinger P, Kamala T (2011). "Tissue-based class control: the other side of tolerance". Nature Reviews Immunology. 11: 221–30. doi:10.1038/nri2940.
  • Perez-Diez Ainhoa; Joncker Nathalie T.; Choi Kyungho; Chan William F. N.; Anderson Colin C.; Lantz Olivier; Matzinger Polly (2007). "CD4 cells can be more efficient at tumor rejection than CD8 cells". Blood. 109: 5346–5354. doi:10.1182/blood-2006-10-051318. PMC 1890845.

Films

References

  1. 1 2 Oakes, Elizabeth H. (2014-05-14). A to Z of STS Scientists. Infobase Publishing. ISBN 9781438109251.
  2. ↑ "Clever bunny". The Independent. Retrieved 2018-07-27.
  3. 1 2 3 "Polly Matzinger: De conejita playboy a paradigma de la inmunología". Procrastina Fácil (in Spanish). 2018-04-29. Retrieved 2018-07-27.
  4. ↑ DREIFUS, CLAUDIA (June 16, 1998). "A Conversation With Polly Matzinger; Blazing an Unconventional Trail to a New Theory of Immunity". Nytimes.com. Retrieved 19 Jan 2015.
  5. 1 2 Oakes, Elizabeth H. (2007). Encyclopedia of World Scientists. Infobase Publishing. ISBN 9781438118826.
  6. ↑ "Laboratory of Immunogenetics | NIH: National Institute of Allergy and Infectious Diseases". www.niaid.nih.gov. Retrieved 2018-07-27.
  7. ↑ "Polly Matzinger, Ph.D., T-Cell Tolerance and Memory Section, Laboratory of Immunogenetics, NIAID, NIH". .niaid.nih.gov. 2013-03-27. Retrieved 2013-08-01.
  8. ↑ NIH. "NIH VideoCasting and Podcasting". videocast.nih.gov. Retrieved 2018-02-06.
  9. ↑ Matzinger P (2013-03-25). "Friendly and dangerous signals: is the tissue in control?". Nat. Immunol. 8: 11–3. doi:10.1038/ni0107-11. PMID 17179963. Retrieved 2013-08-01.
  10. ↑ Russell E. Vance2 (2000-08-15). "Cutting Edge Commentary: A Copernican Revolution? Doubts About the Danger Theory". Jimmunol.org. Retrieved 2013-08-01.
  11. ↑ "URI biotech student awarded Fearless Scientist Scholarship by Institute for Immunology & Informatics". today.uri.edu. Retrieved 2018-07-27.
  12. ↑ Polly Matzinger; Galadriel Mirkwood (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 (1): 84&ndash, 92. doi:10.1084/jem.148.1.84. PMC 2184911. PMID 78964.
  13. ↑ Anton, Ted. Bold Science: Seven Scientists Who Are Changing Our World. New York: WH Freeman, 2000.
  14. ↑ "Scientific Sins". The Scientist Magazine®. Retrieved 2018-07-27.
  15. ↑ "Death By Design". Strange Attractions. Retrieved 2013-10-17.
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