Research at HMS
Cancer cells express unusually high levels of TRPA1, a calcium channel protein. Research by cell biologists at HMS recently showed why: Tumor cells use TRPA1 to defend against toxic cellular byproducts known as reactive oxygen species.
Normally, TRPA1 acts to alert the body to environmental irritants that could be harmful. Eat something exceptionally spicy, for example, and tears may follow in reaction to TRPA1’s alarm. This response has earned TRPA1 the nickname “the wasabi receptor.”
Not only do the findings show how critical a defense against oxidative stress is to cancer’s progression, they also offer insight into the protein’s role in the disease and, possibly, in new treatments.
Brugge JS, et al., Cancer Cell, June 2018
Summing the Parts
Annually, nearly two million people worldwide become infected with HIV-1. Yet, during the more than 30-year search for a safe, effective, long-acting vaccine against the virus, only four concepts have been developed, none of which has been licensed for use. Now, a promising fifth has been reported by an international team led by HMS researchers at Beth Israel Deaconess Medical Center. The vaccine, a mosaic built of genetic sequences drawn from various HIV strains and tested in both humans and nonhuman primates, induced robust responses and was well-tolerated. In the nonhuman animals, it provided 67 percent protection against the acquisition of infection. Phase two trials of the vaccine are now planned.
Barouch DH, et al., The Lancet, July 2018
The Power of One
Researchers studying the human microbiome face a chicken-and-egg problem when comparing the bacterial mix from a healthy gut with that from a diseased gut: Do they attribute any differences to the disease changing the microbiome or the microbiome changing and altering the host health or disease state? HMS scientists, probing how molecules produced by gut bacteria influence mouse metabolism, found that the deletion of a single gene in a strain of the Bacteroides bacterium caused significant metabolic changes and lowered weight gain in the animals. The finding is an early step in work toward developing treatments for metabolic diseases that target the microbiome.
Devlin AS, et al., eLife, July 2018
Aging and Cancer
Some of the first known inherited genetic variants that significantly raise a person’s likelihood of developing clonal hematopoiesis have been identified by researchers at HMS and the Harvard T.H. Chan School of Public Health. This age-related condition is marked by the accumulation of genetically abnormal white blood cells. Such cells may become cancerous or contribute to inflammation in atherosclerotic plaques, a potent risk factor for heart attacks and strokes.
The researchers note that although clonal hematopoiesis is increasingly seen as an important biomarker of risk for future illness, little has been known about what causes the condition. The study brings new clarity by showing the specific sequence of genetic events that give rise to the abnormal blood cells. It also shows that inherited and acquired mutations are more connected than previously thought.
Acquired mutations are thought to occur randomly over time by either appearing spontaneously or after exposure to damaging agents such as ultraviolet light. Yet the team found examples where inherited variants led to the appearance of specific acquired mutations later in life or gave white blood cells with such mutations a growth advantage over other cells.
Clonal hematopoiesis occurs when a single blood stem cell acquires mutations that cause it to produce more than its share of new cells, including white blood cells. Over time, the mutants outcompete normal blood cells, either by proliferating more rapidly or surviving longer. These genetically dominant blood cells are called clones.
With more research, scientists will be able to better assess the risks each clone confers and use that knowledge to develop environmental or medical interventions that might slow the growth of clones and avert disease.
McCarroll SA, Price AL, et al., Nature, July 2018
Image: Behindlens/Essentials/Getty (top); Seth Pincus, Elizabeth Fischer, and Austin Athman/NIAID/NIH (HIV); NIAID/NIH (E. coli); Nephron/Wikimedia Commons (CC 3.0)