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New approach to Epstein-Barr virus and resulting diseases

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New approach to Epstein-Barr virus and resulting diseases


The Epstein-Barr virus can cause a spectrum of diseases, including a range of cancers. Emerging data now show that inhibition of a specific metabolic pathway in infected cells can diminish latent infection and therefore the risk of downstream disease, as reported by researchers from the University of Basel and the University Hospital Basel in the journal Science.

Exactly 60 years ago, pathologist Anthony Epstein and virologist Yvonne Barr announced the discovery of a virus that has carried their names ever since. The Epstein-Barr virus (EBV) made scientific history as the first virus proven to cause cancer in humans. Epstein and Barr isolated the pathogen, which is part of the herpesvirus family, from tumor tissue and demonstrated its cancer-causing potential in subsequent experiments.

Most people are carriers of EBV: 90% of the adult population are infected with the virus, usually experiencing no symptoms and no resulting illness. Around 50% become infected before the age of five, but many people don’t catch it until adolescence. Acute infection with the virus can cause glandular fever — also known as “kissing disease” — and can put infected individuals out of action for several months. In addition to its cancerogenic properties, the pathogen is also suspected to be involved in the development of autoimmune diseases such as multiple sclerosis.

As yet, no drug or approved vaccination can specifically thwart EBV within the body. Now, a research group from the University of Basel and the University Hospital Basel has reported a promising starting point for putting the brakes on EBV. Their results have been published in the journal Science.

EBV hijacks the metabolism of infected cells

Researchers led by Professor Christoph Hess have deciphered how the immune cells infected with EBV — the so-called B cells — are reprogrammed. Known as “transformation,” this process is necessary for the infection to become chronic and cause subsequent diseases such as cancer. Specifically, the team discovered that the virus triggers the infected cell to ramp up the production of an enzyme known as IDO1. This ultimately leads to greater energy production by the power plants of infected cells: the mitochondria. In turn, this additional energy is needed for the increased metabolism and the rapid proliferation of B cells reprogrammed by EBV in this way.

Clinically, the researchers focused on a group of patients who had developed EBV-triggered blood cancer following organ transplantation. To prevent a transplanted organ from being rejected, it is necessary to weaken the immune system using medications. This, in turn, makes it easier for EBV to gain the upper hand and cause blood cancer, referred to as post-transplant lymphoma.

In the paper, which has now been published, the researchers were able to show that EBV upregulates the enzyme IDO1 already months before post-transplant lymphoma is diagnosed. This finding may help to develop biomarkers for the disease.

Second chance for a failed drug

“Previously, IDO1 inhibitors have been developed in the hope that they could help to treat established cancer — which has unfortunately turned out not to be the case. In other words, there are already clinically tested inhibitors against this enzyme,” explains Christoph Hess. Accordingly, this class of drugs might now receive a second chance in applications aimed at dampening EBV infection and thereby tackling EBV-associated diseases. Indeed, in experiments with mice, IDO1 inhibition with these drugs reduced the transformation of B cells and therefore the viral load and the development of lymphoma.

“In transplant patients, it’s standard practice to use drugs against various viruses. Until now, there’s been nothing specific for preventing or treating Epstein-Barr virus associated disease,” says Hess.



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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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