Phosphoric acid (H₃PO₄) and related compounds are found almost everywhere in living systems. They are key components of DNA and RNA, part of cell membranes, and central to ATP, the molecule that stores and transfers energy in cells. These compounds play a major role in moving positive charges, also known as protons. Beyond biology, phosphoric acid is widely used in technologies such as batteries and fuel cells because of its exceptional ability to conduct protons.

How Protons Travel Through Molecules

Protons move through phosphate-containing materials in a unique way. Instead of traveling freely, they hop from one molecule to another. Hydrogen bonds act as pathways that guide this movement. This process, known as “proton-shuttling,” allows charges to move very quickly.

While scientists have long understood that proton-shuttling occurs, the exact molecular details have remained unclear. To investigate this, researchers from the Department of Molecular Physics at the Fritz Haber Institute, along with collaborators from Leipzig and the United States, focused on a key molecular structure involved in this process. Their goal was to identify how the earliest steps of proton transfer actually take place.

Studying Proton Transport at Extreme Cold

Previous research suggested that a specific negatively charged molecule could initiate the proton-shuttling process. This molecule, known as the deprotonated dimer H₃PO₄·H₂PO₄^–, became the focus of the study.

To examine it in detail, scientists created the molecule in the lab and cooled it to extremely low temperatures. By placing it inside a helium nanodroplet, they reduced its temperature to just 0.37 degrees above absolute zero. At this temperature, unwanted disturbances are almost completely eliminated. This allowed the researchers to analyze its structure with high precision using infrared spectroscopy.

The experimental results were combined with quantum chemical calculations, which help predict how molecules are arranged and how they behave. Together, these approaches provided a clearer picture of the molecule than either method alone.

A Single Structure Emerges

The findings revealed an unexpected result. Theoretical models had predicted that the molecule could exist in two equally likely structures. However, the experimental data showed only one stable configuration.

This structure is relatively rigid and features three hydrogen bonds connected through a shared oxygen atom. It also presents high barriers that limit how easily protons can move within it. Similar bonding patterns have been observed in other phosphoric acid clusters, suggesting that this arrangement may be a common structural feature.

These results highlight an important point. Even advanced theoretical models can miss key details, making experimental verification essential for understanding molecular structures.

Why This Discovery Matters

This research helps explain the molecular basis of phosphoric acid’s remarkable proton conductivity, often described as “Nature’s proton highway.” By identifying a single, well-defined structure for the key anionic dimer H₃PO₄·H₂PO₄^–, scientists now have a better understanding of how protons move through these systems.

The findings also provide a valuable reference point for improving quantum chemical models of phosphate-based molecules. In addition, they could guide the development of new materials with enhanced proton conductivity, which are important for technologies like fuel cells. At the same time, the work deepens our understanding of how proton transfer operates in biological systems.

Key highlights

• What they studied: Researchers focused on a pair of phosphoric acid molecules known as an ionic dimer. This small but powerful system plays a major role in moving positive charges inside living organisms and is also widely used in technologies like fuel cells. The goal was to understand what makes it so remarkably efficient at transporting charge.
• How they studied it: To capture an ultra-clear view of the molecule, the team cooled it to an extreme temperature of just 0.37 Kelvin. At this near absolute zero condition, they used infrared spectroscopy along with quantum chemical calculations to map its structure with exceptional precision.
• What they discovered: Instead of finding two possible structures as predicted by theory, the experiments revealed only one stable form. This structure features a specific hydrogen bonding arrangement that closely matches patterns seen in other phosphoric acid systems, suggesting a common structural design.
• Why it matters: The findings help explain the molecular foundation of Nature’s proton highway, the process that allows phosphoric acid to conduct protons so efficiently. This deeper understanding could guide the development of better energy materials and improve our knowledge of how charge transfer works in living systems.

This method could deepen understanding of how complex brain networks are organized and how they function. It may also shed light on what goes wrong in neurological disorders and how diseases like Alzheimer’s develop over time.

“When engineering a computer, you need to know the circuitry of the central processing unit. If you don’t know how everything is wired together, you can’t understand its function, optimize it or fix it when something breaks. We are approaching the brain the same way,” said study leader Boxuan Zhao, a professor of cell and developmental biology at the University of Illinois Urbana-Champaign.

“Our technology enables simultaneous mapping of thousands of neural connections with single-synapse resolution — a capability that doesn’t exist in any current technology. It is directly applicable to understanding circuit dysfunction in neurodegenerative diseases and could provide a platform for developing circuit-guided therapeutic interventions,” he said.

The findings were published in the journal Nature Methods.

A Faster, More Detailed Way To Map the Brain

Mapping the brain has traditionally been slow and difficult. Scientists often had to slice brain tissue into extremely thin sections, image them with microscopes and piece together the pathways manually. While newer sequencing-based tools can label many neurons at once, they usually show where a neuron extends rather than identifying the exact cells it connects with at the synapse, Zhao said.

To overcome this limitation, Zhao’s team created a new platform called Connectome-seq. It assigns each neuron a unique RNA “barcode.” Specialized proteins carry these barcodes from the neuron’s main body to the synapse, the point where two neurons meet.

Researchers then isolate these synapses and use high-throughput sequencing to read which barcode pairs are found together. This reveals which neurons are directly connected, allowing scientists to map networks on a large scale.

Turning Brain Wiring Into a Sequencing Problem

“We translated the neural connectivity problem into a sequencing problem. Imagine a big bunch of balloons. The main body of each balloon has its unique barcode stickers all over it, and some move down to the end of the string. If two balloons are tied together at the end, the two barcodes meet at the junction,” Zhao said. “Then we snip out the knots and sequence the barcodes in each one. If the same knot has stickers from balloon A and balloon B, we know these two balloons are tied together. We are doing this in the brain, just on the level of thousands of neuron cells. With this information, we can reconstruct a sophisticated map that represents the connections among all these seemingly floaty groups.”

Discovering New Brain Circuit Connections

Using Connectome-seq, the team mapped more than 1,000 neurons in a mouse brain circuit known as the pontocerebellar circuit, which links two brain regions. The analysis revealed previously unknown patterns of connectivity, including direct links between cell types that had not been known to connect in the adult brain.

“With improvements already underway in our lab, we are confident that we can make it even better and eventually reach the goal of mapping the whole mouse brain,” Zhao said.

Potential To Transform Alzheimer’s and Brain Disease Research

Because it is both fast and scalable, Connectome-seq could significantly accelerate research into neurodegenerative diseases, psychiatric conditions and other brain disorders. By comparing brain connections in healthy individuals with those at different stages of disease, scientists may be able to identify early changes in neural circuits.

“With sequencing-based approaches, the time and cost are greatly reduced, which really makes it possible to see differences in different brains. We could see where connections change, where the most vulnerable parts of the brain are, perhaps before symptoms even appear,” Zhao said. “For example, if we can catch where exactly the weak link is that kick starts the whole catastrophic cascade in Alzheimer’s disease, can we specifically strengthen those connections to where the disease slows or does not progress?”

The research was supported by a Neuro-omics Initiative grant from Wu Tsai Neurosciences Institute of Stanford University, as well as funding from the Elsa U. Pardee Foundation and the Edward Mallinckrodt Jr. Foundation.

In a proof-of-principle study conducted in mice over six years, the team showed that interrupting a key step in meiosis, the process that produces sex cells, can temporarily halt sperm production without causing lasting harm.

The findings were published today (April 7) in the Proceedings of the National Academy of Sciences.

To achieve this, scientists used JQ1, a small molecule inhibitor originally developed to study cancer and inflammatory diseases. While JQ1 is not suitable as a treatment due to neurological side effects, it is known to interfere with a stage of meiosis called prophase 1. This allowed researchers to demonstrate, for the first time, that targeting meiosis can safely and reversibly shut down sperm production.

“We’re practically the only the group that’s pushing the idea that contraception targets in the testis are a feasible way to stop sperm production,” said Paula Cohen, professor of genetics and director of the Cornell Reproductive Sciences Center.

“Our study shows that mostly we recover normal meiosis and complete sperm function, and more importantly, that the offspring are completely normal,” Cohen said.

Why New Male Birth Control Options Are Needed

Current male contraceptive options remain limited to condoms and vasectomies. While vasectomies are considered long-term, many men hesitate to undergo the procedure, even though reversal surgery is sometimes possible. At the same time, researchers have been cautious about developing hormonal approaches, partly due to safety concerns observed in women.

Cohen and her team focused on meiosis rather than other stages of sperm development to ensure that sperm production could be fully stopped while still allowing it to recover later. This approach also preserves overall reproductive health.

“We didn’t want to impact the spermatogonial stem cells, because if you kill those, a man will never become fertile again,” Cohen said. Also, once sperm entered spermiogenesis, there was a potential for viable sperm to leak out and fertilize an egg.

How JQ1 Temporarily Disrupts Fertility

JQ1 works by disrupting meiosis during prophase 1, causing developing cells to die at that stage. It also blocks the gene activity required for later stages of sperm development.

In the study, male mice received JQ1 for three weeks. During this time, sperm production stopped completely, and key features of meiosis, including chromosome behavior during prophase 1, were disrupted.

Once the treatment ended, recovery began. Within six weeks, most normal meiotic processes returned, along with healthy sperm production. The researchers then bred the mice and confirmed that they were fertile. Their offspring were also healthy and able to reproduce.

“It shows that we recover complete meiosis, complete sperm function, and more importantly, that the offspring are completely normal,” Cohen said.

What a Future Male Contraceptive Could Look Like

If developed for human use, this type of male contraceptive could be delivered as an injection given every three months or possibly as a patch to maintain effectiveness, Cohen said.