Isegoria

Researchers have adapted a third technique, commonly used to chart much larger proteins, to determine the precise shape of small organic molecules:

The gold standard for determining chemical structures has long been x-ray crystallography. A beam of x-rays is fired at a pure crystal containing millions of copies of a molecule lined up in a single orientation. By tracking how the x-rays bounce off atoms in the crystal, researchers can work out the position of every atom in the molecule. Crystallography can pinpoint atomic positions down to less than 0.1 nanometers, about the size of a sulfur atom. But the technique works best with fairly large crystals, which can be hard to make. “The real lag time is just getting a crystal,” says Brian Stoltz, an organic chemist at the California Institute of Technology (Caltech) in Pasadena. “That can take weeks to months to years.”

The second approach, known as nuclear magnetic resonance (NMR) spectroscopy, doesn’t require crystals. It infers structures by perturbing the magnetic behavior of atoms in molecules and then tracking their behavior, which changes depending on their atomic neighbors. But NMR also requires a fair amount of starting material. And it’s indirect, which can lead to mapping mistakes with larger druglike molecules.

The new approach builds on a technique called electron diffraction, which sends an electron beam through a crystal and, as in x-ray crystallography, determines structure from diffraction patterns. It has been particularly useful in solving the structure of a class of proteins lodged in cell membranes. In this case, researchers first form tiny 2D sheetlike crystals of multiple copies of a protein wedged in a membrane.

But in many cases, efforts to grow the protein crystals go awry. Instead of getting single-membrane sheets, researchers end up with numerous sheets stacked atop one another, which can’t be analyzed by conventional electron diffraction. And the crystals can be too small for x-ray diffraction. “We didn’t know what to do with all these crystals,” says Tamir Gonen, an electron crystallography expert at the University of California, Los Angeles (UCLA). So, his team varied the technique: Instead of firing their electron beam from one direction at a static crystal, they rotated the crystal and tracked how the diffraction pattern changed. Instead of a single image, they got what was more like molecular computerized tomography scan. That enabled them to get structures from crystals one-billionth the size of those needed for x-ray crystallography.

Gonen says because his interest was in proteins, he never thought much about trying his technique on anything else. But earlier this year, Gonen moved from the Howard Hughes Medical Institute’s Janelia Research Campus in Ashburn, Virginia, to UCLA. There, he teamed up with colleagues, along with Stoltz at Caltech, who wanted to see whether the same approach would work not just with proteins, but with smaller organic molecules. The short answer is it did. On the chemistry preprint server ChemRxiv, the California team reported on Wednesday that when they tried the approach with numerous samples, it worked nearly every time, delivering a resolution on par with x-ray crystallography. The team could even get structures from mixtures of compounds and from materials that had never formally been crystallized and were just scraped off a chemistry purification column. These results all came after just a few minutes of sample preparation and data collection. What’s more, a collaboration of German and Swiss groups independently published similar results using essentially the same technique this week.

Scientists are starting to understand the biology of bravery:

Most of the science focuses on the amygdala, the almond-shaped structure deep in the brain (one on each side) that generates such feelings as fear and anxiety. In 2005, a team led by Gleb Shumyatsky at Rutgers University reported in the journal Cell that stathmin, a protein produced by the STMN1 gene, has an important role in the amygdala. Mice that were bred not to have the protein explored more of a new environment. They lacked what the researchers called “innate fear” and were unable to form memories of fear-inducing events.

The researchers also manipulated the gene as a kind of “volume” control, producing different levels of stathmin, which in turn resulted in different levels of fear in the mice. In 2010, researchers led by Burkhard Brocke at the Institute of Psychology II in Germany found that people with an exaggerated response to fear had mutations in the gene that controls this volume switch.

As for how we overcome fear, scientists have found brain structures that appear to resist the prompting of the amygdala. In a 2010 study published in the journal Neuron, the neurobiologist Uri Nili at the Weizmann Institute in Israel scanned the brains of research subjects who were afraid of snakes as they decided whether or not to move a live snake closer or farther away on a conveyor belt. The more people were able to overcome their fear and move the snake closer, the more activity they showed in the sgACC, a brain region that sits between the amygdala and the hypothalamus, which stimulates the release of hormones. A control group that wasn’t scared of snakes didn’t show such activity.

Hormones released in the amygdala itself also have been shown to affect bravery. Oliver Bosch, a neurobiologist at the University of Regensburg in Germany, studies maternal instinct in mammals and has found that oxytocin is released in the amygdala when a mother faces a danger to herself and her children. This hormone, in turn, blocks the production of a hormone called CRH, which primes the body for action but can generate feelings of fear and anxiety. It is this sort of hormonal override that would have given Angie Padron, the mother in Florida, the instant courage to confront her assailants. As she herself said of the incident, her instincts just kicked in.

Indeed, taking the amygdala entirely out of the picture can virtually eliminate fear. Justin Feinstein, a clinical neuropsychologist at the Laureate Institute for Brain Research at the University of Tulsa, works with three women, known in the literature just by their initials, who have Urbach-Wiethe disease, a rare genetic disorder that destroys the amygdala. One of them, SM, has never experienced fear in her adult life. A man once threatened her by putting a gun to her head and shouting “Bam!” She didn’t flinch.

Of course, it’s not necessary to have a brain disorder in order to control one’s fear, even in the face of heart-stopping danger. Consider Alex Honnold, the climber who has scaled the 3,000-foot El Capitan in Yosemite National Park without ropes (as featured in the new documentary, “Free Solo”) and made other notable ascents. In 2016, Mr. Honnold’s brain was scanned by neuroscientist Jane Joseph at the Medical University of South Carolina in Charleston. When exposed to images that excite the amygdala in most people, his brain scans showed no response. What’s unclear is whether this capacity predates and enables his daredevil climbing or has been created by it.

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But the amygdala isn’t the only candidate for controlling fear. In a study published earlier this month in the journal Nature Communications, Sanja Mikulovic and colleagues at Uppsala University in Sweden showed that cells called OLM neurons produce theta brain waves, which are seen during meditation and when you feel safe despite a threat in the environment. By manipulating those cells in laboratory mice, the scientists were able to dial up a mouse’s willingness to venture into unexplored areas and tamp down its indications of anxiety, even when smelling a cat. Nicotine also stimulates OLM neurons in humans, a reason that some people chain-smoke to relieve stress.

We know, too, that training and conditioning alters pathways in the brain and can help to mitigate stress and promote calm in fearful situations. A study published in the journal PLOS Biology last year showed, for example, how training instills a kind of autopilot setting. Researcher Sirawaj Itthipuripat at the University of California, San Diego, measured brain activity when people were learning a task and found that less was needed after training, though improvement in performance remained. Another recent paper connected that idea to how people respond to uncertainty and threats. A team of German and Greek researchers completed a nine-month longitudinal study, published in the journal Science Advances, that showed some forms of training changed structures in the cortex and reduced secretions of the stress hormone cortisol.

Military training is partly designed to hold fear in check when carrying out missions that risk death and injury, as well as in the case of disaster. Dave Henson’s training before he deployed to Afghanistan helped him to stay composed while detecting and disarming improvised explosives. Then, a year into his tour, Mr. Henson stepped on an IED. He lost both of his legs.

Once the immediate shock of the blast receded, he found himself reciting the process that he had been trained to follow in the event of a casualty scenario. “The training definitely kicked in,” he says; it distracted him from the pain.