October 5, 2018, by Brigitte Nerlich
Cars and cancer: Metaphorical musings on the occasion of the Nobel Prize in Physiology or Medicine
Metaphors are weird. They are crucial for the expansion of human knowledge. However, they don’t really impart knowledge. They only tell a story. And that story can only be understood by people who already have some knowledge.
When I say ‘life is a journey’, I expect people to understand that metaphor, as people generally know what a journey is. They can understand the ‘target domain’ (life) through the lens of their knowledge of the ‘source domain’ (journey). However, there are limitations to how much a metaphor can increase one’s knowledge or understanding. These limits are set by how much one already knows about the (generally more familiar and concrete) source domain and the (generally less familiar and abstract) target domain. This makes the use and understanding of metaphors in science especially tricky. Think about the metaphor: ‘DNA is a code’…..
The Nobel announcement
This was brought home to me yet again when the Nobel prizes were announced this week. Rony Armon tweeted me the announcement of the Nobel Prize in Physiology or Medicine and said “Check this (textual/visual) metaphor”. And so I did and went down a metaphorical rabbit hole.
This year the prize went to James Allison and Tasuku Honjo ‘for their discovery of cancer therapy by inhibition of negative immune regulation.’ The text of the announcement, which is full of car-related metaphors, is accompanied by an image of the front interior of a car showing molecules hovering over the handbrake and the foot brake. It has the subtitle: ‘Cancer therapy: Releasing the breaks of immunity’. The press release also contains a visualisation of both Allison’s and Honjo’s cancer therapy mechanisms showing various types of pedals being pressed. Overall then we seem to have a metaphor at work here which is based on mapping aspects of cars onto aspects of cancer/cancer therapy, in particular immune cells.
My source domain knowledge of cars is limited but adequate, whereas my target domain knowledge of cancer therapy and biochemistry is more or less zero. That made understanding the car metaphors used to publicise the Nobel prize an interesting challenge. In order to fill my knowledge deficits, I read quite a few blogs and articles and gradually homed in on a smidgen of understanding.
Cars and cancer
Normally, our immune system stops us from getting ill, for example from a cold virus. However, cancer is a problem for it, as cancer is cunning. To explain what cancer does and how the Nobel Prize winners Allison and Honjo managed to out-cun it, I read some useful info provided by Sheena Cruickshank, an immune specialist working at the University of Manchester:
“Immune cells need to be very tightly controlled to stop them being switched on inappropriately and causing inflammation. Cells in our immune system have a series of on and off switches that work in harmony to help regulate their function. The off switches – called ‘checkpoints’ – are a bit like the brakes on your car. This immune balancing act generally works well, but not in the case of cancer tumours. Tumours can encourage the immune brakes to stay on, which means our immune response is dampened and the immune cells cannot kill the tumour effectively. By exploiting knowledge of how immune cells work, the researchers found that they could help the immune cells attack the tumour. The treatment works by releasing the brakes from specific immune cells called T cells. This allows the T cells to stay switched on and releases them to kill the tumour cells.” (Italics mine)
This is what is meant by ‘releasing the brakes of immunity’, the metaphor used in the Nobel announcement, a metaphor that was picked up by almost all the reports on this achievement.
Here is a video explaining it all! And another! And a nice blog post! And a whole book, The Beautiful Cure…so much to learn! (Here one can find not only the brake metaphor but other metaphors too such as ‘masking the immune system’s alarm signals’ etc. etc.).
The important thing about all this is that the two researchers found a way of making something happen by stopping the thing that is stopping it, so to speak. Allison and Honjo found two such mechanisms which can now be used in cancer therapy either separately or in combination.
All this is only the tip of the knowledge AND metaphor iceberg surrounding immunotherapy for cancer. Let’s now dive a little bit more deeply into the science and the metaphors it uses.
History, science and metaphors
The history of cancer therapy began at the end of the 19th century, in 1890 to be precise, with the work of William Coley who “observed that a patient with an inoperable sarcoma that suffered a Streptococcus pyogenes infection twice obtained complete remission”. This is now called Coley’s toxin or vaccine…In the 1950s Peter Medawar and Macfarlane Burnet studied acquired immunological tolerance and were awarded a Nobel prize in 1960.
In the 1960s T cells were discovered. T cells are a type of white blood cell that looks out for problems such as viruses, infection etc. and then deals with these problems (this and the following information was gleaned from an article published a few days before the Nobel announcement, when Allison received the Albany Medical Center Prize in Medicine; see Contify Life Sciences News, September 26)
In the 1980s and 90s researchers found out how to stimulate T cells to do their work better. In 1983 James Allison was the first scientist to identify the protein structure of the T cells antigen receptor, showing how receptors on T cells initiate T cell activation, essentially acting as an ‘ignition switch’. (Another car metaphor!) In 1985 the US Food and Drug Administration approved the first immunotherapy for cancer.
In 1987 the protein receptor CTLA-4 was identified and in 1995 Allison showed that this receptor functions as an immune checkpoint, i.e. acts as a brake or an off switch so that the immune system doesn’t attack healthy tissue. However, such checkpoints can also prevent the immune system from destroying cancer tumours.
Allison then imagined how this brake could be deactivated (released) and how the immune system could then attack foreign or malignant cells. The therapy developed based on these insights is called ‘checkpoint blockade therapy’. (For similar insights achieved by Honjo, regarding the role of the protein PD-1, read here)
In 2003 Allison gave an interview about the development of a new drug, MDX-010, based on these discoveries (see FD (Fair Disclosure) Wire, June 4, 2003). Let’s see what he says – and note the car metaphors which I’ll highlight:
“… for about 15 years my lab’s been studying T cell activation all the way from recognition on antigen by the T-cell antigen receptor which is kind of like the ignition switch on a car and recognizes very specific things on the surface of a virus infected or tumor cells. The discovery of CE28, which is a positive co-stimulatory molecule which sort of acts like the gas pedal on a car and gets the response going. In 1995, we began to study CTLA4 and showed that its inhibitory function, it’s an important down regulator of T-cell responses. Now we know, due to a lot of subsequent work in my lab and others, that this molecule plays an absolutely critical role in limiting T-cell expansion. In 1996, I reasoned that if we could somehow remove the brakes, if you will, from the system, that we could enhance T-cell responses.” He also spoke of releasing the immune system’s emergency brake …
And here is how he summarised things when he won the Nobel Prize!
The first scientific article I found using a car metaphor in a title was published in 1996: ‘Releasing the brakes on antitumor immune response’.
To understand cancer immunotherapy, we seem to have to understand cars. We have to know what how an ignition key works, a concept that probably links up with one of biochemistry’s core metaphors, namely the lock-and key metaphor (where the lock represents an enzyme and the key represents a substrate). We need to know about gas and brake pedals and handbrakes that can be released. We also have to know about ‘checkpoints’, a metaphor that doesn’t quite fit into this semantic field – but relates to releasing the natural brakes that keep the immune system ‘in check’.
Releasing the brakes on the car metaphors
Car metaphors seem to have become part of biochemistry and immunology parlance. They can be used to convey existing knowledge, but they can also be extended creatively to convey new knowledge. This was brought home to me when I came across an article from 2017 entitled “A current perspective on cancer immune theory: step-by-step approach to constructing the magic bullet”.
In the article the authors review research in cancer immunotherapy using various accelerator and brake metaphors. The authors’ novel contribution is couched this way: “In addition to the standard ‘fuel the engine, release the brake’ rules of immunotherapy, we introduce the ‘push the accelerator’ and ‘repair the car’ metaphors to explain part of the current limitations associated with cancer immunotherapy.” The ‘fuel the engine metaphor’ refers to cancer vaccination, while the ‘release the brake’ one refers to cancer therapy by inhibition of negative immune regulation (the focus of this year’s Nobel Prize).
The authors want to combine the two into a ‘magic bullet’, if I understand them correctly, an approach, metaphorically described in the following way (and again I highlight the car metaphors):
“Perplexing is the fact that PD-1 and CTLA-4 checkpoint inhibitors, even when helped by cancer vaccines, are not effective against all cancer types, nor do they work in every patient with the same cancer. Perhaps other immune cell types are negatively affecting cancer immunotherapy? The explanation we put forward to explain this dilemma is that in some cancers we have the machinery (the car) on a downhill slope, so if we release the brake (immune checkpoint inhibitors) the car can move. In contrast, when we are on an uphill slope or on a plain field, releasing the brake simply does not move the car. For such scenarios, we have to release the brake and push the accelerator.”
Don’t put the brakes on basic research
There is clearly still a lot do and think about, metaphorically and otherwise. One thing is for sure. We should not put the brakes on basic research. As James Allison said after receiving the Nobel Prize: “I didn’t get in to this to cure cancer, I got into this because I wanted to know how T-cells worked”.
To understand how T cells work Allison drew on his knowledge of how cars work. He and others were able to map their source domain knowledge of cars onto the as yet unknown target domain of T cells and cancer and in doing so they created a new metaphor and new knowledge, in fact a really intricate and complex system of knowledge. For those, like me, not in the know, the car metaphors provide entry points that allow us to explore that system of knowledge but we have to learn a lot along the way!
Metaphors may be messengers of meaning, but they can only fly on the wings of knowledge.
All this has implications for science communication, but this post is already too long. However, if you are interested you can read an older post of mine where I explore this issue a bit more: Paddling in the shallow end of knowledge.