Clarifying cell function
CAMBRIDGE, U.K.—Cells and their myriad components and functions are incredibly complex, and it often seems that every discovery begs another question. But each answer also brings with it new avenues to pursue in understanding and potentially treating disease, as is the case with a pair of discoveries from researchers at the Wellcome Sanger Institute and collaborating organizations.
One of those discoveries is centered around the nature of clones, communities of cells that are all descendants of a single stem cell. DNA mutations that occur as cells grow, age and replicate are passed from parent cells to daughter cells. In some cases, those mutations occur in oncogenes—genes known to play a role in cancer development—and such mutations enable the clones to expand at a faster pace than normal cells. Previous work by the Wellcome Sanger Institute revealed that clones compete against each other, which prevents cancer development, and a more recent study by Wellcome Sanger, the University of Cambridge and their partners revealed how exactly that competition occurs.
Using genetic lineage tracing and ultradeep sequencing—as well as diethynitrosamine, a mutagen found in tobacco smoke—the research team tracked mutations in esophageal epithelium in mice. Their work revealed that the interplay between mutant clones was based on their mutations and those of any neighboring cells.
“Transgenic lineage tracing revealed strong clonal competition that evolved over time. Clone dynamics were consistent with a simple model in which the proliferative advantage conferred by positively selected mutations depends on the nature of the neighboring cells. When clones with similar competitive fitness collide, mutant cell fate reverts towards homeostasis, a constraint that explains how selection operates in normal-appearing epithelium,” the authors explained in their paper.
The tissue of the esophagus, like skin, is comprised largely of clone cells by the time an individual reaches middle age. As such, understanding how such cells interact could potentially help scientists to intervene on the development of cancer in those tissues.
“In human tissue, there is limited space; clones compete for it and the rule of survival of the fittest applies. If we can rig the game against ‘bad’ clones that may go on to form cancer, and in favor of their more benign neighbors, the bad clones will be replaced,” explained Prof. Phil Jones, lead author of the study from the Wellcome Sanger Institute and the MRC Cancer Unit, University of Cambridge. “By understanding the rules of the game, we can seriously consider how we can intervene and prevent some cancers arising.”
The second discovery is centered on the immune system, specifically T cells. This work comes from a team of scientists from Wellcome Sanger, Open Targets, Biogen, GlaxoSmithKline and other collaborators, and their results were published in Nature Communications.
T cells learn how to fight viruses or bacteria as the immune system is challenged, which then creates memory T cells that retain their experience and can more rapidly confront the same threat if it reappears. The research team analyzed blood samples from healthy volunteers and pinpointed which genes were activated in given T cells, then tested them with cytokines to recreate an immune response. They found that similar to training an animal to respond to a command, the more often a T cell is triggered by a specific immune signal, the further along its memory T cell development is and the faster it could respond to that signal the next time.
It also plays a role in how memory T cells respond to different signals. When naive T cells and experienced memory cells were exposed to transforming growth factor, the former produced regulatory T cells to calm the immune response, while the latter produced more chemicals that cause inflammation.
“Our results showed that the gene expression programs induced in response to cytokines differ substantially between TN [naive T cells] and TM [memory T cells]. Whilst TN constitute a uniform cell population, TM are composed of subpopulations including central (TCM) and effector (TEM) memory cells, as well as effector memory cells re-expressing CD45RA (TEMRA) ... we reasoned that the observed CD4+ T cell continuum reflected the potential of cells to initiate a rapid and robust response upon stimulation, i.e. cells which express more chemokine and cytokine in the resting state will be able to rapidly secrete them upon stimulation. We refer to this property as effectorness,” the authors reported.
Dr. Gosia Trynka, senior author from the Wellcome Sanger Institute and Open Targets, said: “We were surprised to see how flexible and complex the memory T cells’ response could be. Understanding this varied T cell response could help us understand our response to infections such as viruses, and also give clues to what is going wrong in immune diseases such as asthma and type 1 diabetes. By understanding the pathways involved in normal immune response, we aim to find better drug targets for developing new medicines.”