Brain gain as Cambridge scientist scoops global prize

His work, which explores how the brain balances ‘activate’ and ‘inhibit’ signals through receptors called Type-A GABA receptors (GABA A Rs), has earned him the coveted Science & SciLifeLab Prize for Young Scientists. The accolade, from Science magazine and Sweden’s SciLifeLab, is one of the world’s top honours for young scientists.

It will be presented tomorrow (Friday, 15th November) at a special ceremony during Nobel Prize week in Stockholm, highlighting the significance of his contribution to science.

Today, Sente is continuing his work at InstaDeep – an AI technology company based in Africa – where he is exploring new applications for his groundbreaking findings in neuroscience.

Sente also receives $30,000 and three other category winners $10 000 each. All four will have their essays published in Science as well as being invited to Stockholm to present their work and meet other scientists.

The prize is made possible thanks to a donation by the Knut and Alice Wallenberg Foundation: more information about the prize can be found at https://scienceprize.scilifelab.se/

Sente’s findings reveal surprising diversity in the structure of GABA A receptors, which are crucial in regulating brain activity. Each receptor is formed by different arrangements of smaller parts, called subunits, allowing fine adjustments in their function.

These insights could lead to more precise treatments for brain-related conditions such as anxiety and epilepsy by targeting specific receptor types with new medications.

Sente’s research used cryogenic electron microscopy to reveal the molecular structure of GABAA receptors formed by various subunit combinations.

He and his colleagues found that these subunits can assemble in unique ways, creating or removing sites where natural molecules or drugs can bind.

They also discovered that a single neuron can assemble structurally and functionally distinct receptors to respond to combinations of neurotransmitter signals, Sente writes in his prizewinning essay (published on 15th November) in Science.

Valda Vinson, executive editor of the Science family of journals, commented: “Modulating GABAA receptors can have effects ranging from reducing anxiety to inducing euphoria.

“Judges praised the creative work that allowed Dr Sente to explain the complexity that underlies this functional diversity and provides a path to targeted therapeutics.”

Dr Sente added: “GABAARs are already targeted by drugs to treat anxiety, seizures and during general anesthesia. But the new research highlights how specific subunit combinations may create previously unrecognised receptor types, underscoring the need to account for these variations in drug development to avoid unintended binding sites.

“To improve therapies that target GABAA receptors, we really need to understand how these receptors are made in the cell.”

When the neurotransmitter GABA binds to a GABAAR on a signal-receiving neuron, the receiving neuron becomes less active or inhibited. GABA is the primary inhibitory neurotransmitter in the brain, said Sente.

“In addition, the roles of GABAARs are increasingly recognised in peripheral systems, for example in pancreatic and immune signals or in the brain-to-gut communication.”

GABAARs are made up of 19 molecular subunits, and different structures produced by different combinations of these subunits lead to different functions of the receptor. Researchers previously thought there might be about 800 different receptor types.

With new information gleaned from their research, such as the importance of the relative arrangement of subunits, Dr Sente and colleagues calculated there could be as many as 324,727 possible receptor structures.

“I think it is important here to distinguish two related but different questions: which receptors can be assembled, and which do get assembled under physiological conditions,” Dr Sente said.

“In neurons and other tissues expressing GABAARs, assembly is constrained by a number of factors. For example, subunit expression is developmentally programmed, as well as tissue- and cell-type specific.

“It is also possible that in some cases certain subunits never ‘meet’ each other as they are translated in different parts of the cell. However, these regulatory mechanisms could go awry, resulting in aberrant signalling.”

Dr Sente said the assembly of different GABAARs could be dynamically adjusted, possibly through mechanisms that regulate the production of specific subunits at the neuronal synapse.

There are known cases of longer-term adjustment in GABAARs signalling, he added. Levels of the hormone progesterone increase during pregnancy and make GABA activate certain GABAARs more efficiently.

To maintain the balance between activation and inhibition, neurons somehow– Dr Sente said the mechanism is unclear – reduce the number of GABAARs containing a subunit that is sensitive to progesterone.

These receptor numbers usually rebound after pregnancy but if they are slow to recover they can cause an activation-inhibition imbalance that is thought be connected to postpartum depression.

“These insights have inspired one of the better examples of rational drug design in psychiatry: the development of brexanolone, a progesterone analog, which shows remarkable efficacy in treating postpartum depression,” Dr Sente said.

Similar adaptations also result from chronic drug use. A deeper understanding of these adaptation pathways may allow the design therapeutics that do not induce tolerance or dependence.

As a first step toward this goal, Dr Sente and his colleagues determined the structure of a partially assembled GABAAR bound to the assembly factor NACHO, offering the first glimpse into the mysterious process of GABAAR assembly.

These findings are timely, given the growing interest in targeting receptor-associated proteins therapeutically rather than the receptors themselves. For instance, this research could help selectively enhance the neuronal expression of nicotinic acetylcholine receptors (whose assembly is also mediated via NACHO).

Such an approach may offer new therapeutic avenues for Parkinson’s and Alzheimer’s diseases, where the loss of these receptors has been documented, said Dr Sente.

The Science & SciLifeLab Prize for Young Scientists acknowledges that global economic health is dependent upon a vibrant research community that needs to incentivise the best and brightest to continue in their chosen fields of research, as they begin their scientific careers.

Regarding the other 2024 winners is Gabriele Casirati in the molecular medicine category for his essay, “To target, to escape, perchance to cure.” Another is Sabrina Rondeau in the ecology and environment category for her essay, “Digging below the surface.”

Jarrod Shilts is a winner in the genomics, proteomics and systems biology category for his essay, “How to build a human.” Shilts received an undergraduate degree from Vanderbilt University and a Ph.D. from the University of Cambridge.

He then transitioned to a spin-out biotechnology company specialising in the kinds of difficult-to-express proteins he worked with during his doctoral degree. The research group he leads develops technologies to advance the production of new therapeutic proteins.