Every year the editors of Science have an intense discussion to identify the top scientific breakthrough of the year. This year the winner is cancer immunotherapy. This nascent field is just taking baby steps but it is a paradigm shift in the way cancers are treated. The target here is the body’s immune system and not the tumour. The story begins in the late 1980’s when French researchers discovered a new protein receptor on the surface of T cells, called cytotoxic T-lymphocyte antigen 4 (CTLA-4). Then an American scientist, James Allison found that these receptors actually inhibit T cell activity. He wondered whether blocking the blocker — the CTLA-4 molecule — would set the immune system free to destroy cancer. In 1996, he demonstrated that antibodies against CTLA-4 destroyed tumours in rats. Pharma companies initially were wary of this new approach, so a tiny company Medarex in Princeton developed the drug. Finally it was bought over by Bristol-Meyes-Squibs for more than $ 2 billion. For the first time, they demonstrated that any treatment had extended life in advanced melanoma in a randomized trial. Nearly a quarter of participants receiving these antibodies survived at least 2 years.

Meanwhile, a biologist in Japan discovered a molecule expressed in dying T cells, which he called programmed death 1 (PD-1), and which he recognized as another brake on T cells. An oncologist in John Hopkins urged Medarex to develop anti PD-1 antibodies. The results of anti PD-1 antibodies in patients with drug refractory cancers were astounding. However oncologists are still trying to understand how they work and what they do. Some tumours actually grow before shrinking and some tumours continue to shrink even when antibodies have been stopped. Another therapy is called chimeric antigen receptor therapy, or CAR therapy — a personalized treatment that involves genetically modifying a patient’s T cells to make them target tumor cells. For physicians accustomed to losing every patient with advanced disease, these therapies bring a hope they couldn’t have dreamed of a few years ago. (Science 20 December 2013)

Another of the top breakthrough’s listed in science is a new imaging technique called CLARITY. It stands for Clear, Lipid-exchanged, Anatomically Rigid, Imaging/immunostaining compatible, Tissue hYdrogel. It is used on biopsies or post-mortem samples to study highly detailed pictures of the protein and nucleic acid structure of organs, especially the brain. First a series of chemical treatments are applied so that the lipid content of the sample is removed, while all of the original proteins and nucleic acids are left in place.The aim is to make the tissue transparent so that a detailed microscopic analysis of the protein scaffolding may be done. The imaging is done using immunostaining with fluorescent tags. An example of a discovery made through CLARITY imaging is a peculiar ‘ladder’ pattern where neurons connected back to themselves and their neighbors, which has been observed in animals to be connected to autism-like behaviors. Scientists predict CLARITY will be a powerful tool to study neurological disorders with a 3 dimensional perspective. (Science 20 December 2013)