The week’s most astounding developments from the neobiological frontier.

May 20, 2021

Overcoming your family history of dementia

Not surprisingly, one of the strongest risk factors for predicting dementia is having a family history of it. But a surprising and encouraging presentation at an American Heart Association conference this week suggests history is not destiny. Following 302,239 approximately 60-year-old men and women in the UK Biobank for an average of eight years, a team from Iowa State University found that adopting at least three healthy lifestyle behaviors, like maintaining low weight, eating a healthy diet, regularly exercising, getting good sleep, only moderately drinking, and not smoking could lower the odds of developing dementia, even in the face of familial risk. AHA Epi|Lifestyle 2021

Promising new chronic pain research

People who carry loss-of-function mutations in their SCNA9 genes, which code for Nav1.7 channel proteins in the brain, show profound insensitivity to pain. That simple fact has made this system a tantalizing, if so far elusive, molecular target for chronic pain treatments that could be alternatives to highly intoxicating and addictive opioid drugs on the market. Help developing such new drugs could come from new animal models described this week by researchers at the drug company Merck, who found a way to closely monitor the modulation of Nav1.7 channels in live rhesus macaques as they titrated blood levels of experimental drugs designed to inhibit the proteins and relieve pain. Science Translational Medicine

How to do better science

In the constant forward march of human knowledge, the publication of false results is like the construction of bridges to nowhere—a waste of time at the very least and at worst, evidence of willful scientific misconduct and malfeasance. Scientists in many fields have raised concern in recent years that the publish-or-perish culture of modern laboratories actually rewards reporting false positive results, and this problem is reinforced by scientific journals that favor attention-grabbing headlines or “gratuitously novel” but insignificant findings, according to researchers at University of St. Andrews in Scotland and the University of Pennsylvania. This week those researchers published recommended fixes to promote better science within institutions. Nature Human Behavior

Massive genomic study of people with bipolar disorder

Bipolar disorder affects the moods, sleep, energy, thoughts, and behaviors of some 50 million people worldwide, and because it’s a complex mental illness that involves many different genes, its basic biology has been elusive, and new therapy targets have been hard to find. A large genome-wide association study (GWAS) published this week compared complete DNA sequences of 41,917 people with bipolar disorder who were of European ancestry in Europe, North America, and Australia to 371,549 controls. The study found 64 genomic loci associated with bipolar disorder, and expression data implicated 15 specific genes linked to the disease. Some of these genes encode what may be druggable protein targets such as HTR6, MCHR1, DCLK3, and FURIN. Nature Genetics

One-and-done CRISPR shot lowers cholesterol in monkeys

The promise of therapeutic approaches based on CRISPR was on full display this week after a team of researchers at the University of Pennsylvania gave four cynomolgus (“crab-eating”) monkeys a single infusion of CRISPR base editors suspended in lipid nanoparticles. They designed the treatment to target liver PCSK9, a gene that regulates cholesterol levels. The gene has a known variant present in 2-3 percent of some human populations where a single nucleotide change significantly reduces blood cholesterol and protects against atherosclerotic cardiovascular disease, the leading cause of death worldwide. In the monkeys, the proof-of-concept, one-and-done treatment almost completely eliminated the gene in the liver, reduced levels of PCSK9 protein in the bloodstream, and reduced LDL cholesterol in the blood by more than half—changes that remained steady for at least eight months post-injection. Nature

Cloudy with a chance of crushing chest pain

A few massive retrospective population studies in the past that looked at what times of year people in places like Berlin and Los Angeles are most likely to suffer heart attacks have found they peak in December and January but drop to their lowest incidence in the summer months—an effect experts attribute to cold weather, warm spirits, rich foods, and taxing holiday stress. Now doctors have created a machine learning-based AI for predicting out-of-hospital cardiac arrest in Japan based on meteorological and chronological data. They trained their algorithm on 525,374 cardiac cases that occurred from 2005–2013 and demonstrated its ability to predict with high precision when 135,678 more cases occurred in 2014–2015. Sundays, Mondays, holidays, cold winter days, and days where the temperature changed dramatically were most strongly associated with increased incidence. Heart