Thread by @JSheltzer

Jim Allison’s immunotherapy Nobel Prize this week underscores the power of a model organism that has attracted a ton of criticism in recent years:

Many papers have highlighted areas where mouse biology significantly differs from human biology. And these are true! Mice are not just furry people.

nytimes.com/2013/02/12/sci…
slate.com/articles/healt…

But mice are mammals that breed rapidly, they can be housed humanely at a pretty low cost, and they have about 97% of the same genes that people do.

There are also dozens of tools that have been developed over the years to study biology in the mouse – and the work that led to the Nobel Prize for cancer immunotherapy took advantage of many of them.

Golstein and colleagues initially discovered CTLA-4 as a gene expressed on activated T cells. But it wasn’t at all clear what it actually did.

ncbi.nlm.nih.gov/pubmed/3496540

Some people thought CTLA-4 was a stimulatory receptor on T cells, some people thought it was an inhibitory receptor. Scientists found that antibodies against CTLA-4 tended to activate T cells in vitro… but that phenotype could have multiple explanations.

If you think about it, in vitro, it’s hard to differentiate between antagonistic binding of an inhibitory receptor and agonistic binding of an activating receptor. Both would lead to T cell activation.

ncbi.nlm.nih.gov/pubmed/1334116/
ncbi.nlm.nih.gov/pubmed/7882171/

The way to solve conflicting in vitro biochemistry is with in vivo genetics. Tak Mak’s group did just that. Using standard gene-editing techniques, they created CTLA-4 knockout mice:

ncbi.nlm.nih.gov/pubmed/7481803

In the CTLA-4 knockout mice, T cells wouldn’t stop dividing. Mice got huge spleens and lymph nodes, and they eventually died. This proved that CTLA-4 is a negative regulator of T cell activation.

Jim Allison wanted to know whether you could take advantage of CTLA-4 to turn T cells against cancer. But how do you study the interaction of cancer and the immune system? You can’t do that with HeLa or HEK293 cells.

Allison took advantage of syngeneic mouse cancer models – cell lines that will form tumors in normal mice. These – along with genetically-engineered mouse models – are really the best systems for studying the cancer-immune system interaction.
science.sciencemag.org/content/271/52…

When Allison’s group injected these syngeneic cancer cell lines into mice, they’d rapidly grow and kill the mice. But if he co-administered a CTLA-4 antibody, the mice would survive. Immunotherapy!

That work because the basis for the drug ipilimumab and Allison’s Nobel Prize this year. But you couldn’t have done it with yeast, worms, or flies – you needed mice.