Polly Matzinger
Encyclopedia
Iconoclasm
Iconoclasm is the deliberate destruction of religious icons and other symbols or monuments, usually with religious or political motives. It is a frequent component of major political or religious changes...
ic scientist who proposed a novel explanation of how the immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
works, called the danger model.
Early years
Polly Matzinger took to science from an unusual background career path which included stints as a Playboy BunnyPlayboy Bunny
A Playboy Bunny is a waitress at the Playboy Club. The Playboy Clubs were originally open from 1960 to 1988. The Club re-opened in one location in The Palms Hotel in Las Vegas in 2006...
at a Playboy
Playboy
Playboy is an American men's magazine that features photographs of nude women as well as journalism and fiction. It was founded in Chicago in 1953 by Hugh Hefner and his associates, and funded in part by a $1,000 loan from Hefner's mother. The magazine has grown into Playboy Enterprises, Inc., with...
Club in Denver, a bar waitress, a jazz
Jazz
Jazz is a musical style that originated at the beginning of the 20th century in African American communities in the Southern United States. It was born out of a mix of African and European music traditions. From its early development until the present, jazz has incorporated music from 19th and 20th...
musician, a carpenter
Carpenter
A carpenter is a skilled craftsperson who works with timber to construct, install and maintain buildings, furniture, and other objects. The work, known as carpentry, may involve manual labor and work outdoors....
and dog trainer. 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
University of California, Davis
The University of California, Davis is a public teaching and research university established in 1905 and located in Davis, California, USA. Spanning over , the campus is the largest within the University of California system and third largest by enrollment...
and here she met Professor Robert Schwab, the head of the University's wildlife program
Nature documentary
A natural history film or wildlife film is a documentary film about animals, plants, or other non-human living creatures, usually concentrating on film taken in their natural habitat...
who noticed her talent and persuaded her to take to science.
She eventually went to the University of California, San Diego
University of California, San Diego
The University of California, San Diego, commonly known as UCSD or UC San Diego, is a public research university located in the La Jolla neighborhood of San Diego, California, United States...
for her Ph.D., did post-doctoral work at the University of Cambridge
University of Cambridge
The University of Cambridge is a public research university located in Cambridge, United Kingdom. It is the second-oldest university in both the United Kingdom and the English-speaking world , and the seventh-oldest globally...
, and was a scientist at the Basel Institute for Immunology
Basel Institute for Immunology
The Basel Institute for Immunology was founded in 1969 as a basic research institute in immunology located at 487 Grenzacherstrasse, Basel, Switzerland on the Rhine River down the street from the main Hoffmann-La Roche campus near the Swiss-German border. The institute opened its doors in 1971...
before coming to the National Institutes of Health in Bethesda, Maryland.
Ghost Lab at NIAID
Polly Matzinger is now a section head at the National Institute of Allergy and Infectious DiseasesNational Institute of Allergy and Infectious Diseases
The National Institute of Allergy and Infectious Diseases is one of the 27 institutes and centers that make up the National Institutes of Health , an agency of the United States Department of Health and Human Services...
. Matzinger and her coworkers refer to the lab's name 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 is the T-Cell Tolerance and Memory Section of the Laboratory of Cellular and Molecular Immunology. The ghost lab now hosts 3 post-doctoral researchers .http://www3.niaid.nih.gov/labs/aboutlabs/lcmi/tCellToleranceMemorySection/ From this knowledge pool, approximately 0-3 original research articles are published a year, including original research articles and theoretical pieces. A majority of the publications are her taken-author published works, theoretical in nature and published in very highly cited journals. http://www.ncbi.nlm.nih.gov/sites/entrez
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 responseCell-mediated immunity
Cell-mediated immunity is an immune response that does not involve antibodies but rather involves the activation of macrophages, natural killer cells , antigen-specific cytotoxic T-lymphocytes, and the release of various cytokines in response to an antigen...
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
Thomas Kuhn
Thomas Samuel Kuhn was an American historian and philosopher of science whose controversial 1962 book The Structure of Scientific Revolutions was deeply influential in both academic and popular circles, introducing the term "paradigm shift," which has since become an English-language staple.Kuhn...
, Charles Janeway
Charles Janeway
Charles Alderson Janeway, Jr. was a noted immunologist. A member of the National Academy of Sciences, he held a faculty position at Yale University's Medical School and was an HHMI Investigator....
proposed that the old immunological paradigm had reached the limits of its usefulness—or, as he described it, the asymptote
Asymptote
In analytic geometry, an asymptote of a curve is a line such that the distance between the curve and the line approaches zero as they tend to infinity. Some sources include the requirement that the curve may not cross the line infinitely often, but this is unusual for modern authors...
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
Pathogen
A pathogen gignomai "I give birth to") or infectious agent — colloquially, a germ — is a microbe or microorganism such as a virus, bacterium, prion, or fungus that causes disease in its animal or plant host...
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, or stress or "bad cell death" (as opposed to apoptosisApoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
, controlled cell death
Programmed cell death
Programmed cell-death is death of a cell in any form, mediated by an intracellular program. PCD is carried out in a regulated process which generally confers advantage during an organism's life-cycle...
). 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 due to a dynamic and constantly-updated response to danger as defined by cellular damage.
Scope
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 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 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
Autoimmunity
Autoimmunity is the failure of an organism to recognize its own constituent parts as self, which allows an immune response against its own cells and tissues. Any disease that results from such an aberrant immune response is termed an autoimmune disease...
.
Pattern recognition and a tissue-driven immune system
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. They describe these ancient signals as Danger-associated molecular patterns, or DAMPs.In a recent article in Nature Immunology http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&list_uids=17179963&cmd=Retrieve&indexed=google, 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.
Matzinger argues that the idea of DAMPs may explain why Toll-like receptor
Toll-like receptor
Toll-like receptors are a class of proteins that play a key role in the innate immune system. They are single, membrane-spanning, non-catalytic receptors that recognize structurally conserved molecules derived from microbes...
s 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) which 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.A student sitting in an immunology class today will likely hear many phrases coined by Matzinger (like "professional antigen-presenting-cell" or "danger signal" or "DAMPs" (damage associated molecular patterns") 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. Others believe that the immune system is not a single system at all, and is instead a set of mechanisms "cobbled together" by evolution.http://www.jimmunol.org/cgi/content/full/165/4/1725 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.
Past and current work with dogs
In one of her first publications, she appeared to have a dog as a coauthor for a paper for the Journal of Experimental Medicinehttp://www.jem.org/cgi/reprint/148/1/84.pdf. As 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 HoundAfghan Hound
The Afghan Hound is one of the oldest sighthound dog breeds. Distinguished by its thick, fine, silky coat and its tail with a ring curl at the end, the breed acquired its unique features in the cold mountains of Afghanistan, where it was originally used to hunt hares and gazelles by coursing them....
, Galadriel Mirkwood. Once discovered, papers on which she was a major author were then barred from the journal until the editor died and was replaced by another.
Although no dogs have been coauthors of any of her recent papers, she is an avid sheepdog trainer, and, with her two Border Collie
Border Collie
The Border Collie is a herding dog breed developed in the Anglo-Scottish border region for herding livestock, especially sheep. It is the most widespread of the collie breeds....
s, Charlie and Lily, was on the team that represented the United States at the 2005 World Sheepdog Finals in Tullamore, Ireland. She is one of the featured scientists (along with one of her sheepdogs) in the 1995 science documentary
Documentary
A documentary is a creative work of non-fiction, including:* Documentary film, including television* Radio documentary* Documentary photographyRelated terms include:...
Death by Design/The Life and Times of Life and Times
Death by Design/The Life and Times of Life and Times
Death by Design/The Life and Times of Life of Times is a science documentary directed by Peter Friedman which focuses on cytology, i.e. the study of cells, with an emphasis on cell death and aging...
.
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 cellB cellB cells are lymphocytes that play a large role in the humoral immune response . The principal functions of B cells are to make antibodies against antigens, perform the role of antigen-presenting cells and eventually develop into memory B cells after activation by antigen interaction...
s 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). B cells turn off virgin but not memory T cellsMemory T cellsMemory T cells are a subset of infection- as well as potentially cancer-fighting T cells that have previously encountered and responded to their cognate antigen; thus, the term antigen-experienced T cell is often applied. Such T cells can recognize foreign invaders, such as bacteria or viruses,...
. 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 cellCytotoxic T cellA cytotoxic T cell belongs to a sub-group of T lymphocytes that are capable of inducing the death of infected somatic or tumor cells; they kill cells that are infected with viruses , or are otherwise damaged or...
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 cellDendritic cellDendritic cells are immune cells forming part of the mammalian immune system. Their main function is to process antigen material and present it on the surface to other cells of the immune system. That is, dendritic cells function as antigen-presenting cells...
s. 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-helperT helper cellT helper cells are a sub-group of lymphocytes, a type of white blood cell, that play an important role in the immune system, particularly in the adaptive immune system. These cells have no cytotoxic or phagocytic activity; they cannot kill infected host cells or pathogens. Rather, they help other...
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.
- Matzinger, P. (2007). Friendly and dangerous signals: is the tissue in control? Nature Immunol,8,11-13.
- Ainhoa Perez-Diez, Nathalie T. Joncker, Kyungho Choi, William F. N. Chan, Colin C. Anderson, Olivier Lantz, and Polly Matzinger. (2007). CD4 cells can be more efficient at tumor rejection than CD8 cells. Blood, 109, 5346-5354.5346]
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 RocheLa RocheLa Roche may refer to:*Hoffmann-La Roche*La Roche College*Sophie von La Roche, a German writer-Places:*Belgium**La Roche-en-Ardenne, a small town in the Ardennes*Switzerland**La Roche, Fribourg**Roche, Vaud*France...
studio, Basel, SwitzerlandBaselBasel or Basle In the national languages of Switzerland the city is also known as Bâle , Basilea and Basilea is Switzerland's third most populous city with about 166,000 inhabitants. Located where the Swiss, French and German borders meet, Basel also has suburbs in France and Germany...
- 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. Commissioned by the National Association of Science WritersNational Association of Science WritersThe National Association of Science Writers was created in 1934 by a dozen science journalists and reporters in New York City. The aim of the organization was to improve the craft of science journalism and to promote good science reportage....
for a meeting of television producers. NIH special events department and Capitol Studios
- Death By Design. Peter Friedman and Jean-François Brunet (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 MosleyMichael MosleyMichael Mosley is an American television and film actor, best known for playing Drew in the revamped version and final season of the American medical comedy Scrubs.-Early life:...
(1997) (Film, 60 minutes) a ‘Horizon’ program made for public televisionPublic broadcastingPublic broadcasting includes radio, television and other electronic media outlets whose primary mission is public service. Public broadcasters receive funding from diverse sources including license fees, individual contributions, public financing and commercial financing.Public broadcasting may be...
featuring and delineating the Danger model. British Broadcasting CorporationBBCThe British Broadcasting Corporation is a British public service broadcaster. Its headquarters is at Broadcasting House in the City of Westminster, London. It is the largest broadcaster in the world, with about 23,000 staff...
- Microbe Invasion. David GreenDavid Green (director)David Green is a film director, television producer and media executive.Born in London to Evelyn and Louis Green, he was educated at Bury Grammar School and Trinity College, Oxford, where he gained an MA degree in English Language and Literature...
(2001) (Film 60 minutes) a program describing the interrelationship between human bodiesHuman anatomyHuman anatomy is primarily the scientific study of the morphology of the human body. Anatomy is subdivided into gross anatomy and microscopic anatomy. Gross anatomy is the study of anatomical structures that can be seen by the naked eye...
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 relationshipsSymbiosisSymbiosis is close and often long-term interaction between different biological species. In 1877 Bennett used the word symbiosis to describe the mutualistic relationship in lichens...
within the body. The Learning ChannelTLC (TV channel)TLC is an American cable TV specialty channel which initially focused on educational content. Since 1991 TLC has been owned by Discovery Communications, the same company that operates the Discovery Channel, Animal Planet and The Science Channel, as well as other learning-themed networks...
External links
- Matzinger's laboratory homepage, (NIAID, NIH)
- Matzinger profile in the British Journal of Ophthalmology
- "My Scientific Sins" item in The Scientist magazine
- Matzinger profile in Arthritis Today
- An innate sense of Danger