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Scientists develop most sensitive way to observe single molecules

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Scientists develop most sensitive way to observe single molecules


Scientists at the University of Wisconsin-Madison have developed the most sensitive method yet for detecting and profiling a single molecule — unlocking a new tool that holds potential for better understanding how the building blocks of matter interact with each other. The new method could have implications for pursuits as varied as drug discovery and the development of advanced materials.

The technical achievement, detailed this month in the journal Nature, marks a significant advance in the burgeoning field of observing individual molecules without the aid of fluorescent labels. While these labels are useful in many applications, they alter molecules in ways that can obscure how they naturally interact with one another. The new label-free method makes the molecules so easy to detect, it is almost as if they had labels.

“We’re very excited about this,” says Randall Goldsmith, a UW-Madison professor of chemistry who led the work. “Capturing behaviors at the level of single molecules is an amazingly informative way of understanding complex systems, and if you can build new tools that grant better access to that perspective, those tools can be really powerful.”

While researchers can glean useful information from studying materials and biological systems at larger scales, Goldsmith says that observing the behavior of and interactions between individual molecules is important for contextualizing that information, sometimes leading to new insights.

“When you see how nations interact with each other, it all comes down to interactions between individuals,” says Goldsmith. “You wouldn’t even think of understanding how groups of people interact with each other while ignoring how individuals interact with each other.”

Goldsmith has been chasing the allure of single molecules since he was a postdoctoral researcher at Stanford University more than a decade ago. There, he worked under the chemist W.E. Moerner, who received the Nobel Prize in chemistry in 2014 for developing the first method of using light to observe a single molecule.

Since Moerner’s initial success, researchers around the world have devised and refined new ways to observe these tiny bits of matter.

The method that the UW-Madison team developed relies on a device called an optical microresonator, or microcavity. As its name suggests, the microcavity is an extremely tiny space where light can be trapped in both space and time — at least for a few nanoseconds — where it can interact with a molecule. Microcavities are more commonly found in physics or electrical engineering laboratories, not chemistry labs. Goldsmith’s history of combining concepts from disparate scientific fields was recognized in 2022 with a Polymath award from Schmidt Futures.

Microcavities are built from incredibly small mirrors fashioned right on top of a fiber optic cable. These fiber optic mirrors bounce the light back and forth many times very quickly within the microcavity.

The researchers let molecules tumble into the cavity, let the light pass through it, and can not only detect the molecule’s presence, but also learn information about it, such as how fast it moves through water. This information can be used to determine the molecule’s shape, or conformation.

“Conformation at the molecular level is incredibly important, particularly for thinking about how biomolecules interact with each other,” says Goldsmith. “Let’s say you have a protein and you have some small-molecule drug. You want to see if the protein’s druggable, which is to say, ‘Does the drug have some kind of major interaction with the protein?’ One way you might be able to see that is if it introduces a conformational change.”

There are other ways to do that, but they require large amounts of sample material and time-consuming analyses. With the newly developed microcavity technique, Goldsmith says, “we can potentially build a black-box tool to give us the answer in tens of seconds.”

The team, which included Lisa-Maria Needham, a former postdoctoral researcher who is now a laboratory director at the University of Cambridge, has filed a patent for the device. Goldsmith says the device and methods will now be refined over the next couple of years. In the meantime, he says he and his collaborators are already thinking about the many ways it could be useful.

“We’re excited about many other applications in spectroscopy,” he says. “We hope we can use this as a stepping stone to other ways to learn about molecules.”

This research was primarily funded by the National Institutes of Health (R01GM136981), with resonator construction supported by the Q-NEXT Quantum Center, a U.S. Department of Energy, Office of Science, National Quantum Information Science Research Center, under award number DE-FOA-0002253.



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Prying open the AI black box

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Prying open the AI black box


Artificial intelligence continues to squirm its way into many aspects of our lives. But what about biology, the study of life itself? AI can sift through hundreds of thousands of genome data points to identify potential new therapeutic targets. While these genomic insights may appear helpful, scientists aren’t sure how today’s AI models come to their conclusions in the first place. Now, a new system named SQUID arrives on the scene armed to pry open AI’s black box of murky internal logic.

SQUID, short for Surrogate Quantitative Interpretability for Deepnets, is a computational tool created by Cold Spring Harbor Laboratory (CSHL) scientists. It’s designed to help interpret how AI models analyze the genome. Compared with other analysis tools, SQUID is more consistent, reduces background noise, and can lead to more accurate predictions about the effects of genetic mutations.

How does it work so much better? The key, CSHL Assistant Professor Peter Koo says, lies in SQUID’s specialized training.

“The tools that people use to try to understand these models have been largely coming from other fields like computer vision or natural language processing. While they can be useful, they’re not optimal for genomics. What we did with SQUID was leverage decades of quantitative genetics knowledge to help us understand what these deep neural networks are learning,” explains Koo.

SQUID works by first generating a library of over 100,000 variant DNA sequences. It then analyzes the library of mutations and their effects using a program called MAVE-NN (Multiplex Assays of Variant Effects Neural Network). This tool allows scientists to perform thousands of virtual experiments simultaneously. In effect, they can “fish out” the algorithms behind a given AI’s most accurate predictions. Their computational “catch” could set the stage for experiments that are more grounded in reality.

“In silico [virtual] experiments are no replacement for actual laboratory experiments. Nevertheless, they can be very informative. They can help scientists form hypotheses for how a particular region of the genome works or how a mutation might have a clinically relevant effect,” explains CSHL Associate Professor Justin Kinney, a co-author of the study.

There are tons of AI models in the sea. More enter the waters each day. Koo, Kinney, and colleagues hope that SQUID will help scientists grab hold of those that best meet their specialized needs.

Though mapped, the human genome remains an incredibly challenging terrain. SQUID could help biologists navigate the field more effectively, bringing them closer to their findings’ true medical implications.



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Iron meteorites hint that our infant solar system was more doughnut than dartboard

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Iron meteorites hint that our infant solar system was more doughnut than dartboard


Four and a half billion years ago, our solar system was a cloud of gas and dust swirling around the sun, until gas began to condense and accrete along with dust to form asteroids and planets. What did this cosmic nursery, known as a protoplanetary disk, look like, and how was it structured? Astronomers can use telescopes to “see” protoplanetary disks far away from our much more mature solar system, but it is impossible to observe what ours might have looked like in its infancy — only an alien billions of light years away would be able to see it as it once was.

Fortunately, space has dropped a few clues — fragments of objects that formed early in solar system history and plunged through Earth’s atmosphere, called meteorites. The composition of meteorites tells stories of the solar system’s birth, but these stories often raise more questions than answers.

In a paper published in Proceedings of the National Academy of Sciences, a team of planetary scientists from UCLA and Johns Hopkins University Applied Physics Laboratory reports that refractory metals, which condense at high temperatures, such as iridium and platinum, were more abundant in meteorites formed in the outer disk, which was cold and far away from the sun. These metals should have formed close to the sun, where the temperature was much higher. Was there a pathway that moved these metals from the inner disk to the outer?

Most meteorites formed within the first few million years of solar system history. Some meteorites, called chondrites, are unmelted conglomerations of grains and dust left over from planet formation. Other meteorites experienced enough heat to melt while their parent asteroids were forming. When these asteroids melted, the silicate part and the metallic part separated due to their difference in density, similar to how water and oil don’t mix.

Today, most asteroids are located in a thick belt between Mars and Jupiter. Scientists think that Jupiter’s gravity disrupted the course of these asteroids, causing many of them to smash into each other and break apart. When pieces of these asteroids fall to Earth and are recovered, they are called meteorites.

Iron meteorites are from the metallic cores of the earliest asteroids, older than any other rocks or celestial objects in our solar system. The irons contain molybdenum isotopes that point toward many different locations across the protoplanetary disk in which these meteorites formed. That allows scientists to learn what the chemical composition of the disk was like in its infancy.

Previous research using the Atacama Large Millimeter/submillimeter Array in Chile has found many disks around other stars that resemble concentric rings, like a dartboard. The rings of these planetary disks, such as HL Tau, are separated by physical gaps, so this kind of disk could not provide a route to transport these refractory metals from the inner disk to the outer.

The new paper holds that our solar disk likely didn’t have a ring structure at the very beginning. Instead, our planetary disk looked more like a doughnut, and asteroids with metal grains rich in iridium and platinum metals migrated to the outer disk as it rapidly expanded.

But that confronted the researchers with another puzzle. After the disk expansion, gravity should have pulled these metals back into the sun. But that did not happen.

“Once Jupiter formed, it very likely opened a physical gap that trapped the iridium and platinum metals in the outer disk and prevented them from falling into the sun,” said first author Bidong Zhang, a UCLA planetary scientist. “These metals were later incorporated into asteroids that formed in the outer disk. This explains why meteorites formed in the outer disk — carbonaceous chondrites and carbonaceous-type iron meteorites — have much higher iridium and platinum contents than their inner-disk peers.”

Zhang and his collaborators previously used iron meteorites to reconstruct how water was distributed in the protoplanetary disk.

“Iron meteorites are hidden gems. The more we learn about iron meteorites, the more they unravel the mystery of our solar system’s birth,” Zhang said.



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Supermassive black hole appears to grow like a baby star

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Supermassive black hole appears to grow like a baby star


Supermassive black holes pose unanswered questions for astronomers around the world, not least “How do they grow so big?” Now, an international team of astronomers, including researchers from Chalmers University of Technology in Sweden, has discovered a powerful rotating, magnetic wind that they believe is helping a galaxy’s central supermassive black hole to grow. The swirling wind, revealed with the help of the ALMA telescope in nearby galaxy ESO320-G030, suggests that similar processes are involved both in black hole growth and the birth of stars.

Most galaxies, including our own Milky Way have a supermassive black hole at their centre. How these mind-bogglingly massive objects grow to weigh as much as millions or billions of stars is a long-standing question for astronomers.

In search of clues to this mystery, a team of scientists led by Mark Gorski (Northwestern University and Chalmers) and Susanne Aalto (Chalmers) chose to study the relatively nearby galaxy ESO320-G030, only 120 million light years distant. It’s a very active galaxy, forming stars ten times as fast as in our own galaxy.

“Since this galaxy is very luminous in the infrared, telescopes can resolve striking details in its centre. We wanted to measure light from molecules carried by winds from the galaxy’s core, hoping to trace how the winds are launched by a growing, or soon to be growing, supermassive black hole. By using ALMA, we were able to study light from behind thick layers of dust and gas,” says Susanne Aalto, Professor of Radio Astronomy at Chalmers University of Technology.

To zero in on dense gas from as close as possible to the central black hole, the scientists studied light from molecules of hydrogen cyanide (HCN). Thanks to ALMA’s ability to image fine details and trace movements in the gas — using the Doppler effect — they discovered patterns that suggest the presence of a magnetised, rotating wind.

While other winds and jets in the centre of galaxies push material away from the supermassive black hole, the newly discovered wind adds another process, that can instead feed the black hole and help it grow.

“We can see how the winds form a spiralling structure, billowing out from the galaxy’s centre. When we measured the rotation, mass, and velocity of the material flowing outwards, we were surprised to find that we could rule out many explanations for the power of the wind, star formation for example. Instead, the flow outwards may be powered by the inflow of gas and seems to be held together by magnetic fields,” says Susanne Aalto.

The scientists think that the rotating magnetic wind helps the black hole to grow.

Material travels around the black hole before it can fall in — like water around a drain. Matter that approaches the black hole collects in a chaotic, spinning disk. There, magnetic fields develop and get stronger. The magnetic fields help lift matter away from the galaxy, creating the spiralling wind. Losing matter to this wind also slows the spinning disk — that means that matter can flow more easily into the black hole, turning a trickle into a stream.

For Mark Gorski, the way this happens is strikingly reminiscent of a much smaller-scale environment in space: the swirls of gas and dust that lead up to the birth of new stars and planets.

“It is well-established that stars in the first stages of their evolution grow with the help of rotating winds — accelerated by magnetic fields, just like the wind in this galaxy. Our observations show that supermassive black holes and tiny stars can grow by similar processes, but on very different scales,” says Mark Gorski.

Could this discovery be a clue to solving the mystery of how supermassive black holes grow? In the future, Mark Gorski, Susanne Aalto and their colleagues want to study other galaxies which may harbour hidden spiralling outflows in their centres.

“Far from all questions about this process are answered. In our observations we see clear evidence of a rotating wind that helps regulate the growth of the galaxy’s central black hole. Now that we know what to look for, the next step is to find out how common a phenomenon this is. And if this is a stage which all galaxies with supermassive black holes go through, what happens to them next?,” asks Mark Gorski.



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