Discoveries
Biochemistry/ Biophysics
Biochemistry/ Biophysics
Unlocking the secrets of life itself starts with understanding the most basic building blocks of life, including DNA, RNA, proteins, and carbohydrates—how they form, interact, and move, as well as how they influence health and disease.

Discoveries

IN THIS ISSUE

Immunity
06/2024

Cooperative proteins help the immune system identify and attack invaders

At the front line of the human immune response are cells called macrophages, which are responsible for identifying intruders and then directing how the entire immune system responds. Associate Professor Diana Hargreaves, postdoctoral researcher Jingwen Liao, and colleagues have now discovered a molecular mechanism that helps macrophages mount a coordinated response tailored to a specific immune challenge. Activating macrophages requires the work of three versions of a protein complex called SWI/SNF: cBAF, ncBAF, and PBAF. The researchers discovered that each variant plays a distinct role in initiating macrophages’ responses to intruders and, consequently, how the immune system regulates inflammation. By delineating these SWI/SNF variants, the team has revealed new immune system mechanisms that could be targeted with therapeutics to regulate inflammation associated with conditions like sepsis, cytokine storm, COVID-19, and many more.

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Nature Communications
07/2024

Study reveals key gene protecting plants from harmful metals in soil

The negative impact of human activity on Earth doesn’t just affect our planet’s atmosphere—it goes much deeper, into its soils. For instance, the excessive use of manure and sewage sludge can increase heavy metal concentrations in agricultural land where vital crops are grown. One of these heavy metals is zinc, a micronutrient necessary for plant and animal health. In excess, however, zinc can be extremely damaging to sensitive plant species. In a new study, Professor Wolfgang Busch, former graduate student Kaizhen Zhong, and colleagues identified a gene that helps plants manage excess zinc in the soil. The findings reveal that plants tolerate high levels of zinc by trapping it in their root cell walls, a process that is facilitated by a gene called trichome birefringence, or TBR. Scientists and farmers can now use this information to develop and grow crops that are more resilient to soil contamination. Enhancing plant resilience in this way is a major goal of Salk’s Harnessing Plants Initiative.

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Cell
07/2024

New tools reveal neuropeptides, not fast neurotransmitters, encode danger in the brain

In the split second that you accidentally touch the hot handle of a cast iron skillet, pain and a sense of danger rush in. Sensory signals travel from the pain receptors in your finger, up through your spinal cord, and into your brainstem. Once there, a special group of neurons relays those pain signals to a higher brain area called the amygdala, where they trigger your emotional fear response and help you remember to avoid hot skillets in the future. Researchers assumed this process must be mediated by fast-acting neurotransmitters, but Salk scientists found that this was not the case. Associate Professor Sung Han, postdoctoral researcher Dong-Il Kim, and colleagues created two new tools to study larger, slower molecules called neuropeptides. These allowed the scientists to study their role in the danger circuit in live mice for the first time. Their findings revealed that neuropeptides, not fast neurotransmitters like glutamate, were the main messenger in this danger circuit—and more than one neuropeptide is involved. Their findings may explain why existing medications that target only one neuropeptide are often ineffective, and could inspire the development of new treatments for fear-related conditions like anxiety and post-traumatic stress disorder.

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Cell Metabolism
09/2024

Fuel level low! Energy deficits harm athletes’ health, new research tool reveals how

In 2014, the International Olympic Committee named a syndrome affecting many of its athletes: relative energy deficiency in sport, or REDs. Athletes develop REDs when they consistently expend more energy through their physical activity than they take in through their diet. Over time, this prolonged energy deficit can lead to a wide range of symptoms, including hormonal and reproductive issues, insomnia and fatigue, bone weakness and injury, and a higher risk of anxiety and depression. It’s now estimated that more than 40% of professional athletes have REDs, and the rate could be even higher in recreational athletes and exercisers. Despite its high prevalence, little is known about REDs on a cellular and molecular level—until Professor Satchidananda Panda, postdoctoral researcher Laura van Rosmalen, and colleagues created a landmark mouse model of REDs. By studying these mice, they discovered that REDs affects organ size and gene expression patterns across the entire body. What’s more, the syndrome appears to impact male and female mice differently: In males, kidney health was most significantly impacted, while in females, reproductive health and muscle mass were most affected. This work is helping the researchers identify potential biomarkers to improve REDs diagnosis, and also reveals new molecular targets for future therapeutics to halt, reverse, or prevent the syndrome altogether.

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Neuron
09/2024

A new brain-mapping tool may be the “START” of next-generation therapeutics

When repairing a car, it’s important to understand its basic blueprint and how all the parts connect. Treating brain disorders is no different, except that scientists are still missing key details of the brain’s wiring diagram. To address this, Salk Professor Edward Callaway, former graduate student Maribel Patiño, and colleagues developed a new brain-mapping technology called START. The cutting-edge tool allows neuroscientists to trace the connectivity between different types of brain cells with unprecedented resolution. Using this technique, the researchers became the first to resolve cortical connectivity at the resolution of transcriptomic cell types. The discoveries made with START will help researchers design new therapeutics that can target certain neurons and brain circuits with greater specificity. Such treatments could be more effective and produce fewer side effects than current pharmacological approaches.

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Cell Metabolism
10/2024

Exciting collaboration shows some age-related retinal disease is reversible

Our bodies rely on little molecules called amino acids—aptly nicknamed the building blocks of life—that come together to form proteins and carry out bodily functions like digesting, growing, repairing, and so much more. Maintaining a constant supply of these important amino acids requires participation from the liver, kidneys, and circulatory system. But for people with an age-related retinal disease like macular telangiectasia, important amino acids like serine and glycine are depleted. New research from Professor Christian Metallo, visiting graduate student Esther Lim, Salk colleagues, and collaborators at Lowy Medical Research Institute and Scripps Research has revealed how a partial genetic deletion in an important metabolic enzyme (PHGDH) leads to lower levels of circulating serine, and how this contributes to dysfunction between the brain’s visual and non-visual systems. Importantly, they show that dietary serine supplementation can reverse serine-associated retinopathy and peripheral neuropathies.

Annals of Internal Medicine
10/2024

One in three Americans has a dysfunctional metabolism, but intermittent fasting could help

More than one-third of adults in the United States have metabolic syndrome, a cluster of conditions that significantly raise a person’s risk of heart disease, stroke, and type 2 diabetes. These conditions include high blood pressure, elevated blood sugar, excess abdominal fat, and abnormal cholesterol levels. In a new clinical trial, Professor Satchidananda Panda, staff scientist Emily Manoogian, and colleagues at Salk and UC San Diego found that time-restricted eating—also known as intermittent fasting—could offer significant health benefits to adults with metabolic syndrome. Patients who ate within a consistent eight-to-ten-hour window each day for three months saw improvements in several markers of blood sugar regulation and metabolic function compared to those who received standard treatments. The researchers say that compared to other prescribed lifestyle changes, time-restricted eating could offer a more practical intervention accessible to a wider range of patients.

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Nature
10/2024

Scientists create first map of DNA modification in the developing human brain

A new study has provided an unprecedented look at how gene regulation evolves during human brain development, showing how the 3D structure of chromatin—DNA and proteins—plays a critical role. This work offers new insights into how early brain development shapes lifelong mental health. The study was a collaboration between Professor Joseph Ecker’s lab at Salk and colleagues at UC Los Angeles, UC San Francisco, UC San Diego, and Seoul National University. The team created the first map of DNA modification in the hippocampus and prefrontal cortex—two regions of the brain critical to learning, memory, and emotional regulation, and also frequently involved in disorders like autism and schizophrenia. The researchers hope the data resource, which they’ve made publicly available through an online platform, will be a valuable tool scientists can use to connect genetic variants associated with these conditions to the genes, cells, and developmental periods that are most sensitive to their effects.

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Proceedings
of the National Academy of Sciences
10/2024

Through the looking glass: A cross-chiral reaction challenges our definition of life

Just like your left and right hand exist as mirror images of each other, many biological molecules have their own form of left- and right-handedness, called chirality. On Earth, all RNA exists in a right-handed chiral form. Even when scientists make synthetic left-handed versions, the two groups behave as if on opposite sides of a mirror, unable to interact with each other. But what if they could? What if a molecule could reach through the mirror and interact with the reflected world on the other side? What if this set off a chain reaction that got molecules on both sides working together in ways we’ve never seen before? Using sophisticated bioengineering techniques, Salk President and Professor Gerald Joyce, senior staff scientist David Horning, and colleagues engineered a chemical system in which left- and right-handed versions of an RNA enzyme could effectively “reach through the mirror” and replicate each other exponentially and indefinitely. This is the first evidence of a life-like chemical system that operates on both sides of the mirror of chirality, creating the opportunity to study an entirely new form of biochemical evolution. The achievement could also advance the development of cross-chiral therapeutics, diagnostics, and other biotechnologies.

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Cell Metabolism
11/2024

Cholesterol is not the only lipid involved in trans fat-driven cardiovascular disease

High cholesterol has long been the focus of many heart health campaigns due to its role in forming artery-clogging plaques that can lead to stroke, heart attack, or arterial disease. But new research from Professor Christian Metallo, postdoctoral researcher Jivani Gengatharan, and colleagues recently revealed that another class of lipids, called sphingolipids, can also contribute to arterial plaques and heart disease. When the team tracked the flow of dietary fats throughout the body, they found that trans fats were being metabolized into sphingolipids, and this drove the liver to secrete artery-clogging molecules into the bloodstream. The discovery that sphingolipids, and not just cholesterol, can directly contribute to atherosclerotic heart disease opens up a whole new set of molecules and pathways that could be targeted with new drugs to ward off cardiovascular disease, heart attack, and stroke.

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Nature
11/2024

Superior photosynthesis abilities of some plants could hold key to climate-resilient crops

More than 3 billion years ago, on an Earth entirely covered with water, photosynthesis first evolved in little ancient bacteria. In the following many millions of years, those bacteria evolved into plants, optimizing themselves along the way for various environmental changes. This evolution was punctuated around 30 million years ago with the emergence of a newer, better way to photosynthesize. While plants like rice continued using an old form of photosynthesis known as C3, others like corn and sorghum developed a newer and more efficient version called C4. The difference? C4 photosynthesis is 50% more efficient. Because of this, C4 plants can thrive in hot, dry climates and are among the most productive crop species in the world. However, around 95% of plants still use C3 photosynthesis, a less efficient form that makes them more vulnerable to drought and heat. Now, Professor Joseph Ecker, postdoctoral researcher Joseph Swift, and and collaborators at the University of Cambridge have made a breakthrough in understanding the evolution of C4 photosynthesis. The researchers can now use these findings to drive C4 photosynthesis in important C3 crops like rice, wheat, and soybeans, making them more productive and resilient against our warming climate.

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