From Playboy Model to Danger Model: The (brief) Story of Polly Matzinger

Polly Matzinger may be one of the most influential and important immunologists, even if her research is still a little controversial. She took the already known ‘Self/Non-self’ model by Frank Macfarlane Burnet and Frank Fenner from 1949 and expanded it to incorporate ‘danger signals’. However, her life prior to becoming a world-leading immunologist might be the most unexpected thing about her. Born into an artistic French-Dutch family in La Seyne she grew up playing instruments and composing music alongside her brother and sister, who would themselves go on to become a rock musician and artist, respectively. By the early 70s, she had already done stints as a dog trainer, jazz musician, and a Playboy Bunny, before settling as a cocktail waitress in California. At this point, she had been in and out of studying biology at the University of California. After eleven years, she completed her Bachelor of Science. While working at the bar, her professor, Robert Schwab brought in scientific articles for her to read after she asked him about animal mimicry. Matzinger would later credit Professor Robert Schwab for her foray into science and her life.

While at graduate school, Matzinger began to question the generally accepted idea that the body rejects anything that is ‘non-self’. At first glance, the idea makes sense; the immune system should attack things it does not recognise to keep us healthy. But upon further analysis, it might seem to be counterintuitive. We do not reject food, water, or even foetuses. For example, in organ transplants, it is thought that the body needs immunosuppression so that the immune system does not reject the new organ. But why would the body have evolved for this when not until the mid-20th century, an organ had never been transplanted? Equally, why did the body sometimes attack itself in the case of autoimmune diseases? Matzinger did not pursue this line of thought until ten years later.

Thus, the ‘Danger Model’ was derived. Matzinger proposed that in order for the immune response to be activated, there must first be a ‘danger signal’. This danger signal is emitted by unhealthy cells, which might be stressed or infected or have been mutated or damaged. Examples of danger signals include heat-shock proteins, extracellular matrix breakdown products, and cytokines, as well as other proteins and substances released by these stressed cells. Danger signals, or ‘alarmins’, are detected by dendritic cells, which activate T cells and start the immune response.

While this model was originally met with scepticism, it has gained more and more support over the years, as the research into it expands and deepens. With the ‘Danger

Model’, many routes for potential therapies have opened, including cancer vaccines. Matzinger believes that vaccinations can cure up to 80% of all cancers. If danger signals are induced within tumour cells, the tumour will be visible to the immune system. This is different to the current way that cancer vaccines target the tumour.

In current therapeutic cancer vaccines (as opposed to preventative vaccines), the vaccines induce the immune system by showing them what the cancer cell ‘looks like’. It does this by introducing cancer antigens (or tumour-specific antigens, i.e. a protein that is only on the cancer and not on other healthy cells in the body) to the body and, thus, the immune system. Now that the immune cells have seen and identified the cancer antigens, they can search the body for the antigen, induce an immune response against them, and hopefully kill the cancer cells. This means that if the cancer mutates and the antigen changes, which is not unlikely, the vaccine may cease to have any effect because what the immune system is searching for no longer exists.

In contrast, with this new method, the actual antigen does not matter. The vaccine works by inducing the danger signals, making the tumours visible to the immune system without the need for the tumour-specific antigen to be identified. This means that even if the cancer undergoes mutation, the vaccine will still be active and working, as its effectiveness does not depend on the cancer molecule itself.

In addition to describing the ‘Danger Model’, Matzinger also made a name for herself

when she cited ‘Galadriel Mirkwood’ as her co-author on a paper published in the Journal of Experimental Medicine. What is surprising about this, is that Galadriel Mirkwood is not another scientist, but her pet Afghan Hound. It is unknown why she did this, potentially to challenge the strict and rigid rules in the scientific community, to garner more interest in the paper, or just to be funny. Either way, it got her banned from publishing in the journal for more than ten years, but it certainly made her a scientist with a sense of humour and a memorable story.

Written by Henrietta Owen