Stories is a new series that tells a selection of my personal stories, mostly from the time I was a student or worked as a scientist.
I wrote the draft of this post a year ago. The theme of the Grand Round hosted by Ramona Bates at Suture for a Living “posts that have to do with women in medicine as patients, as providers, as scientists” prompted me to take up the thread.
The present story took place at my first job as a scientist in the early eighties. I worked with Pavol Ivanyi, a well known immunologist, specialized in inbred mice strains and the MHC (Major Histocompatibility Complex, i.e. major transplantation antigens). Once a week we held a sort of Journal Club, that took place in our office, a small and dark room without any windows. There was a table, a blackboard and our desks. Pavol often wore the same brown woolen sweater. We had no computers, not to mention powerpoint presentations. We just had a flip-over and a blackboard.
Once it was my turn. The paper I discussed was written by P. Matzinger as first author and if I remember it well R. Zamoyska.
Little was known at that time about how the immune response reacted to foreign material but not to “self”. The MHC plays a major role in this and P Matzinger had truly original ideas about how this worked.
I guess I must have been nervous, because it was quite a difficult theoretical paper (for me at that time).
Many times I said: “he thinks, he had the bright idea, he proposes, he concludes…”.
After I finished my presentation, Pavol took a deep breath and said frowning:
“…..It is not a HE.”
I gazed with a kind of wonder. He continued with his typical Czech accent, serious but with a twinkle in his eyes.
“It is a SHE” …….
“It is a she and ….… a very beautiful one”
Then he told us that Polly Matzinger, for that was her name, was once a Playboy bunny and a waitress at a bar frequented by scientists. A well known professor noticed her talent and persuaded her to become a scientist and get her PhD.
She appeared to be a very original, but also controversial lady. Pavol knew her well.
Pavol carried on:
“Polly has written a paper together with Galadriel Mirkwood* (see pdf here). Do you know who that is?
I nodded: “No” (how should I know?). The name Galadriel, one of the elves of Lord of the Rings, might have been a hint.
“Mirkwood is her Afghan Hound, it is a dog, She found that her dog was as much involved in research as many other coauthors.”
According to Ted Anton’s book Bold Science, the dog was put on as a coauthor for this Journal of Experimental Medicine paper , because she refused to write in the usual scientific passive voice (‘steps were taken’) but was too insecure to write in the first person (‘I took the steps’). 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 (see Wikipedia).
But as a matter of fact, one of her main ideas originated from observing her sheepdog (she is a sheepdog expert as well, and a jazz musician, carpenter, lab technician and problem-dog trainer). “I suddenly realized that there was a cell in the body which behaves like a good sheepdog – the dendritic cell. The dendritic cell would be activated by a cell dying in its midst and kickstart the immune response. And that puts the model together”. (The Independent)
Polly Matzinger is famous for her Danger Model, published in many prominent journals, like Science, Ann N Y Acad Sci, J Immunol, Transplant Proc, Nature Med, Nature Immunology (see refs).
The BBC even made a Horizon -edition about her and her ideas. Horizon, as you may know, is a current and long-running BBC popular science and philosophy documentary program. She does now how to stand out, although sometimes this desire to stand out can overshadow her skills as a scientist and presenter according to some.
Her Danger theory challenges core beliefs about how our immune system works.
The paradigm developed by Janeway (and the Nobel Price winners Medawar/Burnet) is that non-self (foreign) triggers an immune response, while self does not. According to Polly the “self/non-self” model is not adequate.
A system that attacked everything foreign would lead to the system attacking the food we eat; a mother’s body would reject the foetus it carried. Instead, Matzinger thinks, what the body (and notably the dendritic cells) notices is danger.
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 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.
She emphasize for instance that tumors are often not seen as dangerous and therefore not attacked by the immune system, until they outgrow their blood supply, undergo chemotherapy, or otherwise are harmed. Then the damaged tumor cells release endogenous danger signals that help trigger the adaptive response. (see this excellent blog post at Mystery Rays from Outer Space for more detailed discussion).
Her theory also implies that transplants could be permanently accepted if the danger signals could be blocked at the time of the transplant with a short course of drugs. Indeed some of her experiments point that way.
Others insist that it is not much different from the original theory, if one implies the need of a second signal (danger-signals, besides the recognition of non-self).
However, whether she is right or wrong doesn’t really matter in the long run.
Indeed like she said in the NY times:
“It is said the scientist who is 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 are wrong someone will do the experiments to prove they’re wrong and in the process will learn something about nature. So whether I’m right or wrong doesn’t matter.”
Her truly original ideas have stimulated the progress of science. She is an outstanding scientist. According to her own definition science is ” about describing nature, and so is art: We’re painting nature.(…) Actually, it’s a sandbox and scientists get to play all of our lives.“
She is a scientist who is changing our world.
- 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.
- Ted Anton. Bold Science: Seven Scientists Who Are Changing Our World (Paperback) 193 pages; Publisher: W. H. Freeman (May 1, 2001) ISBN-10: 0716744481 ;ISBN-13: 978-0716744481
- Matzinger P. The danger model: a renewed sense of self. Science. 2002 Apr 12;296(5566):301-5.
- Matzinger P. An innate sense of danger. Ann N Y Acad Sci. 2002 Jun;961:341-2. Review. No abstract available.
- Alpan O, Rudomen G, Matzinger P. The role of dendritic cells, B cells, and M cells in gut-oriented immune responses. J Immunol. 2001 Apr 15;166(8):4843-52.
- Celli S, Matzinger P. Liver transplants induce deletion of liver-specific T cells. Transplant Proc. 2001 Feb-Mar;33(1-2):102-3. No abstract available.
- Guimond M, Veenstra RG, Grindler DJ, Zhang H, Cui Y, Murphy RD, Kim SY, Na R, Hennighausen L, Kurtulus S, Erman B, Interleukin 7 signaling in dendritic cells regulates the homeostatic proliferation and niche size of CD4+ T cells. Nat Immunol. 2009 Feb;10(2):149-57. Epub 2009 Jan 11.