Their expedition didn’t lead them to dark matter, but they still found something that had never been seen before, something that defied explanation. Well, at least an explanation that everyone could agree on.

“It’s been something like a detective story,” said Mittig, a Hannah Distinguished Professor in Michigan State University’s Department of Physics and Astronomy and a faculty member at the Facility for Rare Isotope Beams, or FRIB.

“We started out looking for dark matter and we didn’t find it,” he said. “Instead, we found other things that have been challenging for theory to explain.”

So the team got back to work, doing more experiments, gathering more evidence to make their discovery make sense. Mittig, Ayyad and their colleagues bolstered their case at the National Superconducting Cyclotron Laboratory, or NSCL, at Michigan State University.

Working at NSCL, the team found a new path to their unexpected destination, which they detailed June 28 in the journal Physical Review Letters. In doing so, they also revealed interesting physics that’s afoot in the ultra-small quantum realm of subatomic particles.

In particular, the team confirmed that when an atom’s core, or nucleus, is overstuffed with neutrons, it can still find a way to a more stable configuration by spitting out a proton instead.

Shot in the dark

Dark matter is one of the most famous things in the universe that we know the least about. For decades, scientists have known that the cosmos contains more mass than we can see based on the trajectories of stars and galaxies.

For gravity to keep the celestial objects tethered to their paths, there had to be unseen mass and a lot of it — six times the amount of regular matter that we can observe, measure and characterize. Although scientists are convinced dark matter is out there, they have yet to find where and devise how to detect it directly.

“Finding dark matter is one of the major goals of physics,” said Ayyad, a nuclear physics researcher at the Galician Institute of High Energy Physics, or IGFAE, of the University of Santiago de Compostela in Spain.

Speaking in round numbers, scientists have launched about 100 experiments to try to illuminate what exactly dark matter is, Mittig said.

“None of them has succeeded after 20, 30, 40 years of research,” he said.

“But there was a theory, a very hypothetical idea, that you could observe dark matter with a very particular type of nucleus,” said Ayyad, who was previously a detector systems physicist at NSCL.

This theory centered on what it calls a dark decay. It posited that certain unstable nuclei, nuclei that naturally fall apart, could jettison dark matter as they crumbled.

So Ayyad, Mittig and their team designed an experiment that could look for a dark decay, knowing the odds were against them. But the gamble wasn’t as big as it sounds because probing exotic decays also lets researchers better understand the rules and structures of the nuclear and quantum worlds.

The researchers had a good chance of discovering something new. The question was what that would be.

Help from a halo

When people imagine a nucleus, many may think of a lumpy ball made up of protons and neutrons, Ayyad said. But nuclei can take on strange shapes, including what are known as halo nuclei.

Beryllium-11 is an example of a halo nuclei. It’s a form, or isotope, of the element beryllium that has four protons and seven neutrons in its nucleus. It keeps 10 of those 11 nuclear particles in a tight central cluster. But one neutron floats far away from that core, loosely bound to the rest of the nucleus, kind of like the moon ringing around the Earth, Ayyad said.

Beryllium-11 is also unstable. After a lifetime of about 13.8 seconds, it falls apart by what’s known as beta decay. One of its neutrons ejects an electron and becomes a proton. This transforms the nucleus into a stable form of the element boron with five protons and six neutrons, boron-11.

But according to that very hypothetical theory, if the neutron that decays is the one in the halo, beryllium-11 could go an entirely different route: It could undergo a dark decay.

In 2019, the researchers launched an experiment at Canada’s national particle accelerator facility, TRIUMF, looking for that very hypothetical decay. And they did find a decay with unexpectedly high probability, but it wasn’t a dark decay.

It looked like the beryllium-11’s loosely bound neutron was ejecting an electron like normal beta decay, yet the beryllium wasn’t following the known decay path to boron.

The team hypothesized that the high probability of the decay could be explained if a state in boron-11 existed as a doorway to another decay, to beryllium-10 and a proton. For anyone keeping score, that meant the nucleus had once again become beryllium. Only now it had six neutrons instead of seven.

“This happens just because of the halo nucleus,” Ayyad said. “It’s a very exotic type of radioactivity. It was actually the first direct evidence of proton radioactivity from a neutron-rich nucleus.”

But science welcomes scrutiny and skepticism, and the team’s 2019 report was met with a healthy dose of both. That “doorway” state in boron-11 did not seem compatible with most theoretical models. Without a solid theory that made sense of what the team saw, different experts interpreted the team’s data differently and offered up other potential conclusions.

“We had a lot of long discussions,” Mittig said. “It was a good thing.”

As beneficial as the discussions were — and continue to be — Mittig and Ayyad knew they’d have to generate more evidence to support their results and hypothesis. They’d have to design new experiments.

The NSCL experiments

In the team’s 2019 experiment, TRIUMF generated a beam of beryllium-11 nuclei that the team directed into a detection chamber where researchers observed different possible decay routes. That included the beta decay to proton emission process that created beryllium-10.

For the new experiments, which took place in August 2021, the team’s idea was to essentially run the time-reversed reaction. That is, the researchers would start with beryllium-10 nuclei and add a proton.

Collaborators in Switzerland created a source of beryllium-10, which has a half-life of 1.4 million years, that NSCL could then use to produce radioactive beams with new reaccelerator technology. The technology evaporated and injected the beryllium into an accelerator and made it possible for researchers to make a highly sensitive measurement.

When beryllium-10 absorbed a proton of the right energy, the nucleus entered the same excited state the researchers believed they discovered three years earlier. It would even spit the proton back out, which can be detected as signature of the process.

“The results of the two experiments are very compatible,” Ayyad said.

That wasn’t the only good news. Unbeknownst to the team, an independent group of scientists at Florida State University had devised another way to probe the 2019 result. Ayyad happened to attend a virtual conference where the Florida State team presented its preliminary results, and he was encouraged by what he saw.

“I took a screenshot of the Zoom meeting and immediately sent it to Wolfi,” he said. “Then we reached out to the Florida State team and worked out a way to support each other.”

The two teams were in touch as they developed their reports, and both scientific publications now appear in the same issue of Physical Review Letters. And the new results are already generating a buzz in the community.

“The work is getting a lot of attention. Wolfi will visit Spain in a few weeks to talk about this,” Ayyad said.

An open case on open quantum systems

Part of the excitement is because the team’s work could provide a new case study for what are known as open quantum systems. It’s an intimidating name, but the concept can be thought of like the old adage, “nothing exists in a vacuum.”

Quantum physics has provided a framework to understand the incredibly tiny components of nature: atoms, molecules and much, much more. This understanding has advanced virtually every realm of physical science, including energy, chemistry and materials science.

Much of that framework, however, was developed considering simplified scenarios. The super small system of interest would be isolated in some way from the ocean of input provided by the world around it. In studying open quantum systems, physicists are venturing away from idealized scenarios and into the complexity of reality.

Open quantum systems are literally everywhere, but finding one that’s tractable enough to learn something from is challenging, especially in matters of the nucleus. Mittig and Ayyad saw potential in their loosely bound nuclei and they knew that NSCL, and now FRIB could help develop it.

NSCL, a National Science Foundation user facility that served the scientific community for decades, hosted the work of Mittig and Ayyad, which is the first published demonstration of the stand-alone reaccelerator technology. FRIB, a U.S. Department of Energy Office of Science user facility that officially launched on May 2, 2022 is where the work can continue in the future.

“Open quantum systems are a general phenomenon, but they’re a new idea in nuclear physics,” Ayyad said. “And most of the theorists who are doing the work are at FRIB.”

But this detective story is still in its early chapters. To complete the case, researchers still need more data, more evidence to make full sense of what they’re seeing. That means Ayyad and Mittig are still doing what they do best and investigating.

“We’re going ahead and making new experiments,” said Mittig. “The theme through all of this is that it’s important to have good experiments with strong analysis.”

The study, led by CU Anschutz researchers Andrew Mecca and Giusy Caprara in the laboratory of Anthony Peng, tested a decades-old hypothesis which proposed that the gating spring, a tiny, nanometer-scale protein structure which mechanically opens and closes an ion channel in sensory hair cell cells in response to sound vibrations, can act directly as a controller of the channel’s activity.

Previous work in the auditory field has focused mostly on understanding mechanisms which target the ion channel. This study provides the first evidence that the gating spring itself has the capacity to modulate the sensitivity of the channel.

“This study documents the first time we understand a mechanism that regulates auditory sensitivity on both the molecular and mechanical levels,” says Peng, Ph.D., associate professor at the University of Colorado School of Medicine and senior author of the study. “We uncovered a new mechanism of modulating sensitivity, which opens the door to discovering more about how the auditory system functions generally and uses this to both maximize the range of sounds that we can detect and protect the vital sensory cells from potential damage.”

The mechanism discussed in the study works by modifying a physical property of the gating spring, its stiffness, which is responsible for controlling how much the channel opens and closes in response to sound vibrations that enter the inner ear. The researchers studied the properties of the gating spring and the resulting activity of the channel in single sensory hair cells, and found that cyclic adenosine monophosphate (cAMP), a specific type of signaling molecule, reduced the stiffness of the gating spring and decreased the channel’s sensitivity — which is the first time a physiological mechanism for controlling gating spring stiffness has been identified.

“Identifying the underlying mechanism of this process — how it works physiologically and mechanically, provides an avenue for future research and provides an opportunity for the field to develop a new type of drug that can be used to prevent a type of hearing loss that occurs from exposure to very loud sound,” says Peng. Ultimately, they aim to learn more about how the ear can detect such a large range of sounds and how the system protects itself, and this represents a huge step forward for the field.

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Materials provided by University of Colorado Anschutz Medical Campus. Original written by Kelsea Pieters. Note: Content may be edited for style and length.

Now, new research clarifies the role of these intestinal white blood cells, known as 𝛄𝛅 T cells, in colorectal cancer. It turns out that the cells have a double-edged function: They rein in early-stage tumors but, as the disease progresses, undergo biochemical changes and switch sides, strengthening the tumor. The findings, published in Science, shed further light on the role of 𝛄𝛅 T cells in tumor growth, and may open new paths toward colorectal cancer therapies.

“𝛄𝛅 T cells that live in the gut act to prevent tumor formation,” says Bernardo Reis, a research associate in the laboratory of Daniel Mucida at The Rockefeller University. “But once tumors form, gut 𝛄𝛅 T cell populations change, enter the tumor, and promote tumor growth.”

Altered T cell receptors

The intestinal lining may be the body’s most vulnerable port of entry. Composed of but a single layer of epithelial cells, this busy digestive region must absorb useful substances like nutrients, and reject harmful ones like foodborne pathogens, within a limited working space. 𝛄𝛅 T cells mind the gaps, perpetually scanning the epithelium to maintain the integrity of the intestinal lining and prevent pathogens from invading the rest of the body.

Reis set out to investigate conflicting claims over whether these cells help or hinder the growth of intestinal tumors. But as is often the case in biology, there was no simple answer.

“We had data showing 𝛄𝛅 T cells were protective, but the literature suggested that they also promote tumor growth,” Reis says. “We wanted to understand what these 𝛄𝛅 T cells were really up to.”

Working in a mouse model of colorectal cancer, Reis and colleagues derived 𝛄𝛅 T cells from the intestines of animals with early-stage tumors and from the tumors of mice with advanced cancer. In comparing these two sources of supposedly identical cells, the researchers were surprised to find vast molecular differences between them. For example, the two categories of 𝛄𝛅 T cells boasted different T cell receptors. Moreover, 𝛄𝛅 T cells that had entered the tumor produced IL-17, a cytokine that normally promotes inflammation in response to infection. In the tumor microenvironment, however, IL-17 was promoting disease — spurring tumor growth and recruiting other cells to help hide the tumor from the rest of the immune system.

“The 𝛄𝛅 T cells had completely changed,” Reis says.

To confirm their findings, the team then used CRISPR gene editing technology to selectively remove T cell receptors from the white blood cells, changing the cells from anti-tumor to pro-tumor, or vice versa. In this way, they managed to increase the number and decrease the size of tumors in mouse models. “When we depleted the original 𝛄𝛅 T cells, the mice became sicker,” Reis says. “And when we depleted the tumor invading 𝛄𝛅 T cells, the tumors shrank.”

Hope for human cancers

Reis and colleagues witnessed similar activity in 𝛄𝛅 T cells derived from human colorectal tumors and their environs. Cells inside the tumor resembled the renegade, late-stage 𝛄𝛅 T cells seen in mice, while cells hovering around the outside of the tumor looked more like the original Res. “It almost looked like a fight between these two populations,” Reis says. “Regular cells were trying to contain the tumor while cells inside were promoting tumor growth.”

In the short term, the Mucida lab will focus on shoring up our understanding what promotes 𝛄𝛅 T cells’ shift from the intestine’s stark ally into its source of ruin. Future studies will delve deeper, examining whether it might be possible to modulate normal 𝛄𝛅 T cells to curb the tumor and prevent their cancer-promoting alter egos from dominating the arena. Reis is also interested in exploring ways to manipulate the system by which altered 𝛄𝛅 T cells enter the tumor.

“Perhaps we might one day fashion 𝛄𝛅 T cells into Trojan horses that can act as anti-cancer cells right inside the tumor microenvironment,” he says.

For this purpose, the researchers studied fruit flies of the genus Drosophila, which they had genetically modified in such a way that they cannot form Creld. In the animals, the heart rate was slowed in a characteristic way — a sign of energy deficiency. They also exhibited severe motor disorders. The power plants of the cell, the mitochondria, are responsible for providing energy. Their malfunction can result in the death of nerve cells that are responsible for motor function in humans. The clinical picture is known as Parkinson’s disease.

“So Creld may play an important role not only in impaired heart function, but also in Parkinson’s disease,” says Dr. Nicole Kucharowski of the LIMES Institute, who, along with her colleague Marie Paradis, conducted a key part of the experiments in the study. “The findings of a recent analysis are consistent with this. It suggests that Creld production is often reduced in Parkinson’s patients.” But just how Creld might be related to Parkinson’s was puzzling: The protein is not found in mitochondria at all. It can be detected exclusively in a widely branched network of tubes that serves to produce various molecules in the cell — the endoplasmic reticulum (ER). How can it interfere with the function of cellular power plants from there?

Pesticide suspected of causing Parkinson’s disease

To find out, the researchers administered small amounts of a pesticide to healthy fruit flies (i.e., those that can form Creld). It contains the active ingredient rotenone, which is suspected of triggering Parkinson’s disease in humans. Rotenone acts directly in the mitochondria by inhibiting a key step in energy production. After administration of the pesticide, the flies showed motor disorders similar to those of the Creld mutants. “We also found that their mitochondria are very often in contact with the ER,” Bülow explains.

In further experiments, the researchers were able to show that certain classes of lipids are transported from the ER to the mitochondria during this contact. These so-called phospholipids rekindle the step in energy production that is inhibited by rotenone. With assistance from the ER, the mitochondria try to ramp up the energy supply again in this way. “And the availability of Creld seems to be crucial for this transfer of phospholipids,” Bülow points out. “In flies that cannot form Creld, phospholipids accumulate in the contact sites between ER and mitochondria. So they don’t get transported to the mitochondria, but accumulate.”

Creld increases energy production in the cell

Creld is therefore important for increasing energy production in the cell. This is in line with the observation that Drosophila mutants without Creld produce hardly any hydrogen peroxide in their mitochondria — this is a molecule produced as a waste material during the work of the power plants. Hydrogen peroxide can damage cells. Until now, it was thought that it was produced in excessive amounts in people with Parkinson’s or that it was not adequately disposed of. This would gradually poison the nerve cells responsible for motor function.

It is possible, however, that another effect might cause their demise — namely, the chronic undersupply of energy triggered by damage to or underproduction of Creld. “This is a thesis that we now need to investigate further,” says Bülow, who is a member of the Transdisciplinary Research Area “Life and Health” at the University of Bonn.

The current success is also the result of a successful cooperation. For instance, essential parts of the work were carried out at the University of Osnabrück. Dr. Julia Sellin, who originally helped initiate the study, has also recently moved to the University Hospital in Aachen. “The collaboration with Prof. Dr. Christoph Thiele from the Cluster of Excellence Immunosensation2 here at the University of Bonn also went extremely well,” stresses Bülow.

Funding:

Working groups from the Universities of Bonn and Osnabrück, the University Hospital Aachen and the Leuven Center for Brain and Disease Research in Belgium were involved in the study. The work was funded by the German Research Foundation.

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Materials provided by University of Bonn. Note: Content may be edited for style and length.