Of course, the cell is not powerless in the face of such lesions. It has an extensive catalog of cellular mechanisms that are set in motion following DNA damage. DNA damage response, or DDR for short, is the technical term for this. Specific signaling pathways usually initiate the immediate recognition and repair of DNA damage, thus ensuring the survival of the cell.

A new look at the DNA damage response

A team of scientists from Julius-Maximilians-Universität Würzburg (JMU) in Bavaria, Germany, has now taken a closer look at one of these signaling pathways. The group has identified a new mechanism of the DNA damage response that is mediated via an RNA transcript. Their results help to broaden the conceptual view on the DNA damage response and to link it more closely with RNA metabolism.

Dr. Kaspar Burger, junior research group leader at the Department of Biochemistry and Molecular Biology, was responsible for this study. The group has published the results of their investigations in the journal Genes & Development.

RNA transcripts as regulators of genome stability

“In our study, we focused on so-called long non-coding RNA transcripts. Previous data suggest that some of these transcripts act as regulators of genome stability,” says Kaspar Burger, explaining the background to the work. The study focused on the nuclear enriched abundant transcript 1 — also known as NEAT1 — which is found in high concentrations in many tumor cells. NEAT1 is also known to react to DNA damage and to cellular stress. However, its exact role in the DNA damage response was previously unclear.

“Our hypothesis was that RNA metabolism involves NEAT1 in the DNA damage response in order to ensure the stability of the genome,” says Burger. To test this hypothesis, the research group experimentally investigated how NEAT1 reacts to serious damage to the genome — so-called DNA double-strand breaks — in human bone cancer cells. The result: “We were able to show that DNA double-strand breaks increase both the number of NEAT1 transcripts and the amount of N6-methyladenosine marks on NEAT1,” says the scientist.

RNA modification marks are often deregulated in cancer cells

Methyladenosine marks on RNA transcripts are a topic that scientists have not been dealing with for very long. They fall into the area of epitranscriptomics — the field of biology that deals with the question of how RNA modifications are involved in the regulation of gene expression. Methyl groups play a key role in this. It is known, for example, that RNA modifications are often misplaced in cancer cells.

NEAT1 releases an DNA repair factor

The experiments conducted by Kaspar Burger and his team show that the frequent occurrence of DNA double-strand breaks causes excessive methylation of NEAT1, which leads to changes in the NEAT1 secondary structure. As a result, highly methylated NEAT1 accumulates at some of these lesions to drive the recognition of broken DNA. In turn, experimentally induced suppression of NEAT1 levels delayed the DNA damage response, resulting in increased amounts of DNA damage.

NEAT1 itself does not repair DNA damage. However, as the Würzburg team discovered, it enables the controlled release and activation of an RNA-binding DNA repair factor. In this way, the cell can recognize and repair DNA damage highly efficiently.

According to the scientists, knowledge about the role of NEAT1 methylation in the recognition and repair of DNA damage could open up new therapeutic options for tumors with high NEAT1 expression. However, it must first be clarified whether these results, which were obtained in simple cell systems, can also be transferred to complex tumor models.

Kaspar Burger’s research was supported by the German Cancer Aid and the Mildred Scheel Early Career Center for Cancer Research (MSNZ) in Würzburg.

Whenever cells divide, there is a high risk of damage to the genetic material. After all, the cell has to duplicate its entire genetic material and copy billions of genetic letters before it divides. This repeatedly results in “reading errors” of the genome. However, other factors are also responsible for the accumulation of DNA damage in the course of a person’s life: exposure to sun light, alcohol and cigarettes are just a few examples of factors that are known to damage the genetic material and thus can cause cancer, among other things.

Of course, the cell is not powerless in the face of such lesions. It has an extensive catalog of cellular mechanisms that are set in motion following DNA damage. DNA damage response, or DDR for short, is the technical term for this. Specific signaling pathways usually initiate the immediate recognition and repair of DNA damage, thus ensuring the survival of the cell.

A new look at the DNA damage response

A team of scientists from Julius-Maximilians-Universität Würzburg (JMU) in Bavaria, Germany, has now taken a closer look at one of these signaling pathways. The group has identified a new mechanism of the DNA damage response that is mediated via an RNA transcript. Their results help to broaden the conceptual view on the DNA damage response and to link it more closely with RNA metabolism.

Dr. Kaspar Burger, junior research group leader at the Department of Biochemistry and Molecular Biology, was responsible for this study. The group has published the results of their investigations in the journal Genes & Development.

RNA transcripts as regulators of genome stability

“In our study, we focused on so-called long non-coding RNA transcripts. Previous data suggest that some of these transcripts act as regulators of genome stability,” says Kaspar Burger, explaining the background to the work. The study focused on the nuclear enriched abundant transcript 1 — also known as NEAT1 — which is found in high concentrations in many tumor cells. NEAT1 is also known to react to DNA damage and to cellular stress. However, its exact role in the DNA damage response was previously unclear.

“Our hypothesis was that RNA metabolism involves NEAT1 in the DNA damage response in order to ensure the stability of the genome,” says Burger. To test this hypothesis, the research group experimentally investigated how NEAT1 reacts to serious damage to the genome — so-called DNA double-strand breaks — in human bone cancer cells. The result: “We were able to show that DNA double-strand breaks increase both the number of NEAT1 transcripts and the amount of N6-methyladenosine marks on NEAT1,” says the scientist.

RNA modification marks are often deregulated in cancer cells

Methyladenosine marks on RNA transcripts are a topic that scientists have not been dealing with for very long. They fall into the area of epitranscriptomics — the field of biology that deals with the question of how RNA modifications are involved in the regulation of gene expression. Methyl groups play a key role in this. It is known, for example, that RNA modifications are often misplaced in cancer cells.

NEAT1 releases an DNA repair factor

The experiments conducted by Kaspar Burger and his team show that the frequent occurrence of DNA double-strand breaks causes excessive methylation of NEAT1, which leads to changes in the NEAT1 secondary structure. As a result, highly methylated NEAT1 accumulates at some of these lesions to drive the recognition of broken DNA. In turn, experimentally induced suppression of NEAT1 levels delayed the DNA damage response, resulting in increased amounts of DNA damage.

NEAT1 itself does not repair DNA damage. However, as the Würzburg team discovered, it enables the controlled release and activation of an RNA-binding DNA repair factor. In this way, the cell can recognize and repair DNA damage highly efficiently.

According to the scientists, knowledge about the role of NEAT1 methylation in the recognition and repair of DNA damage could open up new therapeutic options for tumors with high NEAT1 expression. However, it must first be clarified whether these results, which were obtained in simple cell systems, can also be transferred to complex tumor models.

Kaspar Burger’s research was supported by the German Cancer Aid and the Mildred Scheel Early Career Center for Cancer Research (MSNZ) in Würzburg.

Of 236 patients who received cilta-cel infusions at 16 U.S. medical centers in 2022, 89% saw their cancer respond to the treatment and 70% had a complete response, meaning there was no detectable cancer after the treatment. These numbers are comparable to the results of the phase II CARTITUDE-1 trial that led to cilta-cel’s approval by the U.S. Food and Drug Administration (FDA), which showed a 98% response rate and an 83% complete response rate.

Most notable and encouraging, according to researchers, was that over half of the patients included in the new study would have been ineligible to participate in CARTITUDE-1.

“Even though in the real world a majority of patients are not as fit in terms of performance status, organ function, or baseline blood counts as they were in the clinical trial that led to FDA approval [of this therapy], these patients can do very well,” said Surbhi Sidana, MD, the study’s lead author and associate professor at Stanford University School of Medicine. “We saw very high response rates that appeared to be durable, despite over half of the patients not meeting [the trial’s] eligibility criteria. The response rates and time until progression of myeloma or death due to any reason was within the range of results observed in the clinical trial.”

Multiple myeloma is a cancer affecting plasma cells, a type of white blood cell. Currently about 40% of people diagnosed with multiple myeloma do not survive five years, and the prognosis is poorest in patients who do not see their cancer eradicated with standard treatments (refractory) or who see their cancer return after an initial response (relapsed). Two CAR-T therapies, where a patient’s own immune cells are removed, genetically altered, and then infused back into the body to attack and kill cancer cells, have been approved for use in these patients.

Cilta-cel was approved in 2022 for use in patients whose multiple myeloma had not been eradicated or had relapsed after four or more previous lines of therapy; the approval was expanded to earlier lines of treatment in April 2024. The new study focused on patients who had received treatment under the initial approval indication for heavily pre-treated patients. For the new study, researchers retrospectively analyzed outcomes among 255 patients who began the process of receiving cilta-cel in March through December of 2022. The study participants had undergone a median of six prior lines of therapy — and up to 18 lines of therapy — without seeing a lasting response.

Of the 255 patients who started the process of receiving cilta-cel, 236 (about 92%) underwent the full treatment. In addition to analyzing response rates of the whole study population, researchers examined outcomes among several subgroups. They found that patients who received the CAR T-cell product within the range specified by the FDA had a higher response rate (with 94% seeing a response overall and 76% seeing a complete response) compared with the one-fifth of patients whose CAR T cells did not fully conform to the quality standards specified by the FDA.

Researchers also examined a subgroup that included patients who had received prior therapies targeting B cell maturation antigen (BCMA), a protein found on multiple myeloma cells. Since cilta-cel targets BCMA, patients who had previously received such therapies were excluded from the CARTITUDE-1 trial. Researchers found that the 14% of study participants who fell into this category did show lower response rates than those who had not previously received BCMA targeted therapies, with the difference being most pronounced in patients who had received BCMA targeted therapies more recently. This suggests that further studies could help elucidate how the timing of cilta-cel and other BCMA targeted therapies may affect outcomes. The researchers also identified other key patient and disease characteristics that were associated with a lower likelihood of survival or a higher likelihood of disease progression.

Overall, rates of serious side effects were similar to those reported in previous clinical trials. The study found that three-quarters of those who received cilta-cel infusions experienced cytokine release syndrome (CRS), a common CAR-T side effect that can be severe, but only 5% experienced events of grade 3 or higher. Overall, 14% of study participants experienced neurotoxicity and 10% experienced delayed neurotoxicity; 2% experienced Parkinsonism.

“Delayed neurotoxicity is predominantly seen with cilta-cel [compared with other CAR-T therapies], and that’s another trade-off we should still be aware of,” said Dr. Sidana.

The study also found a relatively high rate of death (10%) unrelated to patients’ cancer, mostly from infections or CRS, suggesting that there may be room for improvement in decreasing infection risks and managing CRS.

As a retrospective, real-world study, the study did not include a control group and there may have been discrepancies in outcomes assessment and reporting among the 16 centers that contributed data. Researchers suggested that additional studies could help to identify opportunities to reduce serious side effects and determine whether using cilta-cel earlier during cancer treatment could help to lower the risk of toxicity.

Although a lifetime of immune-suppressing medicine is the standard regimen for transplant recipients, this comes with considerable dangers and side effects, including susceptibility to infection and decreased efficacy of vaccines.

Now, breakthrough research from a new University of Virginia biomedical engineering professor who recently joined both the School of Engineering and Applied Science and the School of Medicine is helping pioneer a new way for the body to accept transplanted organs without compromising the immune system.

Evan Scott is the Thomas A. Saunders III Family Jefferson Scholars Foundation Distinguished University Professor and David Goodman Family Bicentennial Professor of Nanomedicine in the biomedical engineering department, a joint program of UVA’s School of Engineering and Applied Science and School of Medicine, which he joins after 11 years at Northwestern University.

Scott is the co-author of a new article in the journal Proceedings of the National Academy of Science,describing a study in which Scott and fellow researchers used nanoparticles to make the cells of transplanted hearts in mice resistant to attack by their immune system.

“What we’re trying to do is modify the immune system in a controlled and therapeutic way, so that one day transplant patients won’t have to continuously take the immunosuppressive drugs that they do today, with all the risks they entail,” Scott said.

Beyond the area of transplant, Scott’s new lab at UVA will continue this line of research, which could have implications for other areas that deal with immune rejection, such as diabetes, cell therapy, and autoimmune disorders. He’ll also lead UVA’s Institute for Nanoscale Scientific and Technological Advanced Research, or NanoSTAR, as a part of the new Paul and Diane Manning Institute of Biotechnology.

“Evan’s innovative work with nanoparticles represents the kind of forward-thinking science that can reshape entire medical fields. We are thrilled to have him join our UVA community,” said Jennifer L. West, Dean of the School of Engineering and Saunders Family Professor of Engineering.

The Immune System’s Dilemma: Friend or Foe?

There are about 4,000 heart transplants in the United States each year, and the number is on the rise. However, in a significant percentage of cases, the body rejects the transplanted organ, misclassifying it as a threat and sending in the immune system to attack.

Existing treatments focus on one of two paths: suppressing the immune system so that it will not attack — but leaving the patient’s immune system compromised to viral and bacterial threats — or by building tolerance, which helps the body accept the new organ.

Scott and his lab are focused on the second approach; in the new study, he and his coauthors tried to rewire the cellular-level instructions that cause an immune system to attack a new organ, essentially retraining the immune system to tolerate the new cells.

The Role of Myeloid Cells in Organ Rejection

The body’s immune system uses a wide range of white blood cell types to address a diversity of threats and functions, including pathogenic infection, cancer and wound healing. Myeloid cells circulating in the blood stream are a particularly versatile white blood cell, capable of changing into several different forms as required by the task at hand. When they detect a threat, myeloid cells called monocytes can transform into inflammatory macrophages — attack cells that deal with intruders.

Targeting HIF-2α: A New Therapeutic Strategy

Dr. Scott’s long-term collaborator, Dr. Edward Thorp, discovered that these inflammatory macrophages didn’t always develop in response to transplanted cells. They found that a particular protein, HIF-2α, influenced this process, as it was present in the hearts of mice who accepted the transplant, but not present in those that rejected the new heart.

For researchers, this meant that the protein could be therapeutically targeted and used to signal to the host’s immune system that the newly transplanted heart cells were OK and do not need to be attacked, preventing the monocytes from transforming into inflammatory macrophages.

The research team therefore developed nanoparticles encapsulating the drug Roxadustat, which increases the levels of HIF-2α in monocyte. Since the spleen serves as a reservoir for monocytes, this organ was targeted by the nanoparticles to modify circulating white blood cells and maximize the effect of the therapy. This strategy ensured that a sufficient amount of circulating monocytes were modified to signal the immune system to specifically leave the transplanted heart cells alone while allowing the immune system itself to remain otherwise fully functional.

In the study, mice who received the treatment showed significantly better ability to accept their transplanted hearts.

“We specifically targeted the delivery of the drug directly to the spleen, which proved highly effective. This ability to modify how circulating monocytes respond to their environment has an immense and broad therapeutic potential for treating a variety of different disorders,” Scott said.

A team of Rice University chemical engineers led by Lisa Biswal has found that exposing a certain class of such particles — micron-sized beads endowed with a special magnetic sensitivity — to a rapidly alternating, rotating magnetic field causes them to organize into structures that are direction-dependent or anisotropic. The finding is significant because anisotropy can be manipulated to create new, tunable material structures and properties.

“Our key finding is that by alternating the direction of the rotation of the magnetic field after each revolution, we can create an anisotropic interaction potential between particles, which has not been fully realized before,” said Aldo Spatafora-Salazar, a chemical and biomolecular engineering research scientist in the Biswal lab and one of the lead authors on a study about the research published in Proceedings of the National Academy of Sciences.

Dana Lobmeyer, the other first author on the study, explained that the particles under scrutiny in the study are collectively known as superparamagnetic colloids whose responsiveness to magnetic fields makes them a popular building block for high-performance materials with tailored functionality.

“This discovery is significant for bottom-up advanced materials design, especially because we honed in on an aspect of the interaction between the colloids and magnetic fields that is usually overlooked — magnetic relaxation time,” said Lobmeyer, a Rice doctoral alumna advised by Biswal.

The relaxation time refers to the delay in the beads’ magnetic response to changes in field direction. The researchers hypothesized that this delay combined with the effect of the alternating magnetic field affects the beads’ interactions, causing them to arrange into a crystal lattice in two dimensions and to form elongated, aligned clusters in three dimensions.

“The delayed magnetic response, or magnetic relaxation time, of superparamagnetic beads was previously considered negligible, but what we found is that taking it into account and coupling it with the effect of the alternating magnetic field is a powerful way to exercise precise control over the particles,” said Biswal, the corresponding author on the study and Rice’s William M. McCardell Professor in Chemical Engineering, professor of materials science and nanoengineering and senior associate dean for faculty development.

The research involved a combination of experiments, simulations and theoretical predictions. Experimentally, the team looked at both concentrated and dilute bead suspensions combined with alternating magnetic fields of different intensities and frequencies.

“Concentrated beads formed elongated, aligned clusters, and we analyzed how different parameters influenced their shape,” said Spatafora-Salazar. “Dilute suspensions simplified the system, allowing us to study interactions between two beads — a version of the system known as a dimer.”

Experimental insights from dimers helped explain the alignment and elongation in larger clusters. However, experimental data only matched simulations once the magnetic relaxation time measurements (which form the subject of a separate forthcoming study) were taken into consideration.

One fun twist to the data was the Pac-Man shape described by the distribution of a bead’s magnetization: In a magnetized state, each bead acquires a dipole — a pair of negative and positive charges like a north-south axis. In response to a rotating magnetic field, the dipole moves like a compass needle, aligning all the beads along the same orientation. However, due to magnetic relaxation, the needle does not turn a full 360 degrees, leaving what shows up as Pac-Man’s mouth when the data is mapped out.

“The interactions are weakest along the mouth but strongest along the head, causing the alignment of dimers and clusters,” Lobmeyer said. “We would not have been able to understand this phenomenon without deviating from the traditional assumptions used to study these beads.”

Other authors include Rice alumni Lucas H.P. Cunha ’23 and former Rice postdoctoral fellow Kedar Joshi. The research was supported by the National Science Foundation (214112, 1828869) and the ACS Petroleum Research Fund (65274-ND9).

“Given that magic is about the conflict between perceptual processes and our beliefs, we should be able to experience magic in other senses, but it turned out to be really difficult,” says corresponding author Gustav Kuhn, an Associate Professor in Psychology at the University of Plymouth. “If you’re born blind, you’ll likely never have experienced a magic trick. Why is that? Can we create tricks that could be enjoyed and experienced by people with blindness?”

Only a handful of tricks involve other senses, like touch, and virtually none focus solely on auditory perception. But auditory illusions are everywhere. Stereo sound manipulates audio timing between the ears, creating the illusion of sound coming from different directions. Movies use the Shepard tone, an auditory illusion that gives the impression of an endlessly rising pitch, to build unease and tension that keeps the audience on edge.

So, why are auditory magic tricks rare? The researchers argue that the reason may stem from the fundamental differences between how the brain processes visual and auditory information. Humans are visual creatures. We tend to trust what we see more than what we hear, making us more surprised when our vision fools us.

Visual perception also reflects the state of the world, while auditory perception is transient. In other words, sound provides information about an event that has happened. Because magic relies on manipulating the perceived state of the world, this distinction between vision and sound may be at the heart of why auditory tricks are elusive.

“If you see a trumpet, you don’t say ‘I saw a perception of a trumpet,'” says Kuhn. “But if you hear a trumpet, you’re more likely to say, ‘I heard the sound of a trumpet.’ This is the kind of difference we don’t think about.”

Another possibility is that magicians simply never considered creating auditory tricks, though the team believes it’s unlikely given the creativity and history of the craft. Still, to find out, the team launched a competition challenging magicians to conjure tricks using only sound, with results expected in November 2024.

“Magic should not rely on vision alone, and yet it’s nearly impossible to perform a trick that does not involve our visual perception,” says Kuhn. “We don’t fully understand why yet, but this is an interesting question that invites more investigation into our senses and may help make magic more inclusive.”

This work was supported by the Agence Nationale de Recherche grant.

They argue that subsidies can alter market pressures, leading to unintended consequences that not only perpetuate harmful subsidies over time but also diminish the overall effectiveness of those intended to promote environmental sustainability.

Therefore, when they must be used, subsidies should have clear end-dates, advise the authors.

“We’ve got this odd juxtaposition of trying to get rid subsidies in some sectors, and then ramping up subsidies in others,” says lead author Kathleen Segerson, Board of Trustees Distinguished Professor of Economics at the University of Connecticut. “The question that interested me was: is this a good thing or a bad thing?”

Segerson and her coauthors are a group of internationally leading economists, ecologists, geographers, psychologists, and other scientists who convened for the 2022 Askö Workshop sponsored by the Beijer Institute for Ecological Economics in Stockholm, Sweden.

Subsidies can be powerful motivators that further environmental and sustainability goals, say the authors. For example, the United States’ Inflation Reduction Act of 2022 uses tax credits and incentives for things like electric vehicles (EVs), solar power, and wind power to meet its renewable energy and efficiency targets.

They can also be a politically easier approach to enacting change than creating new laws or taxes, says Segerson, and are even sometimes viewed as political capital, to ensure support from particular interest groups.

But some subsidies that appear to encourage sustainability are not so simple, the authors explain. Sometimes they can have negative spillover effects.

Take the case of EVs: Switching from gasoline-powered cars to EVs reduces greenhouse gas emissions. When subsidies for EVs and their technology create more inexpensive EVs, however, that market will expand, increasing overall vehicle use.

“When you’re subsidizing any industry, you’re essentially promoting that industry,” says Segerson.

But if subsidies instead went to increased infrastructure for and access to public transportation, more people might get rid of their cars, making the net positive environmental impact much greater.

“A subsidy that might have initially been viewed as beneficial for society might eventually be recognized as having costs that greatly exceed benefits,” the authors write.

Many subsidies in place for decades have long been identified by economists and environmentalists alike as actively contributing to climate change and biodiversity threats.

The authors cite that U.S. agricultural input subsidies have been shown to drive 17% of nitrogen pollution, while production subsidies account for 14% of global deforestation. In 2018, nearly 70% of $35.4 billion in fishing subsidies went to increasing fishing capacity through aid like fuel purchases, capital investment, and infrastructure, all of which contribute to overfishing.

Despite the leaders of the G20 committing to phasing out inefficient fossil fuel subsidies more than a decade ago, some sources estimate that there were still $1.3 trillion in global fossil fuel subsidies in 2022, owing to the considerable vested interest and political pressure from benefiting corporations to keep them in place.

In the United States, the Biden administration has tried repeatedly to repeal tax breaks for fossil fuels but hasn’t succeeded, leading a New York Times article to call the subsidies “zombies of the tax code: impossible to kill.”

From an economic efficiency perspective, it’s better to tax activities that generate negative effects, such as a carbon tax, says Segerson — but they are a hard sell.

“Environmental taxes are very difficult to get passed, so you’d rather have the subsidy than nothing,” she says.

Subsidies that reduce negative environmental impacts are therefore a second-best solution, she says. Imposing time limits is of great importance to ensure the subsidies that are the best we can do now can be removed when something better is possible.

“We can subsidize these greener production processes, but cautiously, and recognizing that we don’t want to have a reliance on these subsidies over the long term,” says Segerson.