Discoveries

All the cells in an organism have the exact same genetic sequence. What differs across cell types is their epigenetics, meticulously placed chemical tags that influence which genes are expressed in each cell. Mistakes or failures in epigenetic regulation can lead to severe developmental defects. This creates a puzzling question: If epigenetic changes regulate our genetics, what is regulating them? 

Salk scientists, led by biochemist Julie Law, PhD, used plant cells to discover that a type of epigenetic tag called DNA methylation can be regulated by genetic mechanisms. Prior to this study, scientists understood only how DNA methylation could be initiated by other preexisting epigenetic modifications, which didn’t explain how novel methylation patterns could arise. The discovery that the DNA itself can instruct new methylation patterns is a major paradigm shift and helps explain how a cell can modify its epigenetics to grow, respond, and recover. The findings could inform future bioengineering strategies for altering methylation patterns to repair or enhance specific cell functions, with many potential applications in medicine and agriculture. 

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How does our DNA store the massive amount of information needed to build a human being? And what happens when it’s stored incorrectly? Jesse Dixon, MD, PhD, has spent years studying the way this genome is folded in 3D space, knowing that dysfunctional folding can cause cancers and developmental disorders, including autism-related disorders. 

New research from Dixon’s lab adds to a growing understanding that the genome’s 3D organization is constantly in flux. Using different types of human cells, the lab showed that this dynamic genome unfolding and refolding process occurs at different rates in different parts of the genome, which, in turn, influences gene regulation and expression. The findings may point to targets for blocking the dysfunctional folding that leads to cancers and developmental disorders. 

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Why is it that two people can develop the same infection but have dramatically different disease trajectories? Salk scientist Janelle Ayres, PhD, and her colleagues discovered that the kidney plays a key role in filtering inflammatory molecules out of the body after an infection, and the amino acid methionine can improve that filtration. Dietary supplementation of methionine was enough to boost kidney performance in mice and protect against inflammation-related wasting, blood-brain barrier dysfunction, and death. The findings highlight how small dietary changes can lead to big impacts in disease outcomes and could support the use of methionine in future treatments for inflammatory conditions, especially in patients with kidney dysfunction. 

“Our findings add to a growing body of evidence that common dietary elements can be used as medicine. By studying these basic protective mechanisms, we reveal surprising new ways to shift individuals that are fated to develop disease and die onto trajectories of health and survival. It may one day be possible for something as simple as a supplement with dinner to make the difference between life and death for a patient.” 

JANELLE AYRES 

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How can two people infected by the same pathogen have such different responses? It largely comes down to variability in genetics (the genes you inherit) and life experience (your environmental, infection, and vaccination history). These two influences are imprinted on our cells through small molecular alterations called epigenetic changes, which shape cell identity and function by controlling which genes are turned “on” or “off.” Salk scientists, led by Joseph Ecker, PhD, debuted a new epigenetic catalog that reveals the distinct effects of genetic inheritance and life experience on various types of immune cells. The new cell-type-specific database helps explain why people can respond differently to the same illnesses and medications, and could serve as the foundation for more effective and personalized therapeutics.  

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Dealing with an infection isn’t as straightforward as simply killing the pathogen. Our bodies must carefully monitor and steer the immune response to tackle the infection without hurting healthy tissues. If the immune system overreacts and leads to sepsis, this can be more life-threatening than the original infection. 

But our bodies change a lot over the course of a lifetime. Do their mechanisms for regulating and tolerating immune activity change, too? Salk scientists, led by Janelle Ayres, PhD, found that younger and older mice with sepsis have distinct paths through sickness. In fact, the mechanisms that young mice used to survive sepsis were the very same mechanisms that caused older mice to die, suggesting that future therapies may be more effective if tailored to the patient’s age. The researchers say new sepsis treatments are especially needed as the antibiotic resistance crisis continues to threaten existing care strategies. 

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For cancer cells to grow and proliferate, they must be able to rapidly build and renew their outer membranes. These membrane structures are made of fatty molecules called lipids, but technical limitations have made it difficult to measure the dynamics of lipid metabolism. In a new study, Salk scientists, led by Christian Metallo, PhD, used biochemical engineering tools and principles to address this problem. 

The team successfully repurposed a technique traditionally used to model glucose and mitochondrial metabolism to now measure changes in lipid flux in tumors. They collaborated with fellow Salk cancer researcher Reuben Shaw, PhD, to study lung cancer models, identifying specific changes in metabolism depending on the genetic mutations present in a tumor. This technology will now help them identify new therapeutic candidates to target lipid metabolism in cancer and other diseases. 

“What’s really cool about this new technology is that Reuben and I asked these same questions with older technology years ago, so we were especially attuned to the improvements. The new model offers much more detail and is going to allow us to better identify, validate, and target therapeutic candidates in lipid metabolism, lung cancer, and beyond.” 

CHRISTIAN METALLO 

Young minds are easily molded. Each new experience rewires a child’s brain circuitry, adding and removing synaptic connections between neurons. These wiring patterns become more stable with age, but biology has left some wiggle room to ensure that adult brains can still adapt and refine their circuitry as needed. 

Nicola Allen, PhD, and her team have now discovered a molecule that is critical for stabilizing brain circuits in adulthood: a protein called CCN1 secreted by star-shaped cells called astrocytes. Mouse studies showed that CCN1 coordinates the maturation of multiple cell types to reduce the plasticity of the adult brain, but removing it had the opposite effect. The CCN1 pathway could now be a prime target for new therapeutics designed to support learning and plasticity in people with conditions such as Alzheimer’s disease, depression, or PTSD, or to promote neural repair after injury or stroke. 

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Seagrasses preserve our oceans and planet by absorbing carbon dioxide, calming rough waters, and offering a safe harbor for sea life. Unfortunately, these underwater meadows are under threat, and coastal restoration efforts to replant them often fail. 

In the waters of San Diego’s Mission Bay, a new hybrid seagrass has started to grow. The hybrid is a cross between the shallow-water Zostera marina and its deeper-water cousin, Zostera pacifica, whose tolerance for low-light conditions is a favorable trait as coastal waters become increasingly murky. A research team at Salk and UC San Diego, led by plant biologist Todd Michael, PhD, used advanced genomic and transcriptomic technologies to investigate the hybrid seagrass and found that it possesses specific circadian clock genes, inherited from its deep-water relative, that help it tolerate low-light conditions. The scientists say this genomic profile could make the new hybrid seagrass a promising candidate for future “genomically informed” coastal restoration efforts in California and beyond. 

“With these genomic resources, we can replace trial-and-error plantings, which fail in up to 60 percent of Zostera projects, with genomically informed restoration, selecting genome-environment-matched plants to markedly improve establishment and long-term success.” 

TODD MICHAEL 

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