A New Kind of Biology for a New Century

by Lindsay Borthwick

A fundamental shift is underway in the biological sciences, one that hinges on collaboration and big data

The Author

Lindsay Borthwick

The Researchers

Fred “Rusty” Gage
Edward Chang

Neuroscientist Rusty Gage argues that a fundamental shift is underway in the biological sciences, one that hinges on collaboration and big data. That shift can already be seen in the brain research highlighted in this news roundup. Some of Gage’s own research studies, the latest of which is described here, hinges on modelling diseases in the laboratory using human stem cells, a cutting-edge technology he can deploy because of strong collaborations within his institute. Another new study is harnessing the power of big data to develop personalized treatments for depression. And, a set of large-scale projects, planned for a new phase of the U.S. BRAIN Initiative, will bring together collaboration and big data to advance our fundamental understanding of the brain. Neuroscientists, it seems, are seizing the moment.

From left: iPSC-derived dentate gyrus (DG)-like neurons (green) from control subject; bipolar lithium responder; and bipolar lithium nonresponder. While the percentage of DG-like neurons is the same for control and bipolar, the gene activation profiles are different and the nonresponder has low levels of Lef1. Credit: Salk Institute ​

A new kind of biology

Since 2018, neuroscientist Rusty Gage, former co-director of the Kavli Institute for Brain and Mind at UC San Diego and the Salk Institute, has also served as the Salk’s president. In a Q&A to mark both his 25th year at the Salk Institute and its 60th anniversary, Gage talks about collaboration and the future of biological science, which he says is being conducted in a whole new way: “We are beginning to see a new biology that incorporates computation, mathematics and engineering. In this new paradigm, you aggregate data sets from all over the world and build a theoretical model of the concepts you’re interested in, so you can decide what scientific questions to pursue. Here, the model is helping guide you to where the really critical questions are, and answering those questions is not dependent entirely on your personal experience, skills or equipment.” Read more.

Clues to bipolar disorder

Researchers are a step closer to understanding why approximately two-thirds of patients with bipolar disorder don’t respond to the mood-stabilizing drug lithium. An international team of scientists, led by the Salk Institute’s Rusty Gage, PhD, recently showed that decreased activation of a gene called LEF1, which typically helps regulate the activity of neurons, may distinguish lithium responders from non-responders. The researchers grew neurons from blood cells taken from patients with bipolar disorder who responded to the drug and those who didn’t, and compared the gene expression in neurons from those two groups with controls. LEF1 stood out: It was deficient in the neurons of non-responders. An additional set of experiments clarified the role and regulation of LEF1 in the neurons and pointed the way to a potential treatment.

Personalized brain stimulation

Another new study, this time led by researchers at the University of California, San Francisco (UCSF), targets a hard-to-treat neuropsychiatric disorder: depression. Up to 30 percent of patients with depression do not respond to standard treatments, therefore a team of researchers at UCSF have planned a major clinical trial to test whether personalized brain stimulation could help. Recently, the team, led by Katherine Scangos, MD, PhD, reported the results of a case study focused on one patient. Using a new approach, they first identified the brain signatures associated with a patient's symptoms. Then, they stimulated the patient’s brain at different sites and times, and showed it was possible to alleviate distinct symptoms of depression. The new study builds on research by co-senior author and neurosurgeon, Edward Chang, MD, a member of the Kavli Institute for Fundamental Neuroscience. Previously, Chang and his collaborators showed they could map neural activity related to mood fluctuations in patients undergoing surgery for epilepsy. “Our prior work showed a proof of principle for targeted stimulation across brain areas to treat mood symptoms, but an outstanding question has been whether the same approach would hold true for patients with depression alone,” he said in a news release.

Look ahead at the U.S. BRAIN Initiative

In a wide-ranging Q&A, U.S. BRAIN Initiative Director John Ngai, PhD, tells Neuroscience Quarterly about the Initiative’s recent progress, COVID-19’s impact on the BRAIN Initiative, the need to attract diverse talent and how the Initiative could help promote diversity, equity and inclusion in neuroscience. He also talks about three large projects that will launch duriing the Initiative’s next phase: a human brain cell census; a microconnectivity project focused on the mammalian brain; and, a cell type “armamentarium” to develop scalable technologies for studying brain cell types in a wide range of organisms. “I believe [these projects] will transform the way we conduct neuroscience research and apply this knowledge toward cures a human brain,” he says. Read more.

BRAIN Initiative redux

The BRAIN Initiative Alliance also has a new blog post looking back at the scientific and technological breakthroughs of 2020 led by BRAIN Initiative investigators. It also highlights recent preprints that are likely to be published in peer-reviewed journals in 2021, including a map of brain development in the nematode, C. elegans. The Kavli Foundation is a partner in the U.S. BRAIN Initiative, and its U.S.-based neuroscience institutes conduct research aligned with the goals of the Initiative.

Smelly signalling

A new study from researchers at Johns Hopkins University focuses on hydrogen sulphide, a gas with the pungent odor of rotten eggs. The gas is increasingly recognized as an important signalling molecule in the nervous system, which modulates the activity of target proteins through a process called chemical sulfhydration. In the brain, sulfhydration levels decrease with age, especially in patients with Alzheimer’s disease. The new study, co-led by Bindu Paul, PhD, and Solomon Snyder, D.Phil., MD, suggests the noxious gas protects brain cells from Alzheimer’s. Using a mouse model of the neurodegenerative disease, the researchers studied the effect of a hydrogen sulphide-carrying compound, which slowly releases the gas into the bloodstream, on memory and motor function. The animals that received the injection demonstrated improved cognitive and motor function compared to controls. Additional experiments showed that hydrogen sulfide blocks the interaction between a common enzyme called glycogen synthase β (GSK3β) and the tau protein, an interaction that contributes to the accumulation of neurofibrillary tangles—a hallmark of Alzheimer’s—in neurons. Much more research needs to be done to understand the interplay between the gas and GSK3β, as well as other proteins, but the results point toward a new target for Alzheimer’s disease drugs. Synder is a member of the Kavli Neuroscience Discovery Institute.

Written by Lindsay Borthwick


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