Thousands of genes are expressed differently in the brains of men and women, researchers have discovered.
The findings could help explain differences in neurodevelopmental, psychiatric, and neurodegenerative disorders between the sexes.
While men are more likely to experience schizophrenia, attention deficit hyperactivity disorder, and Parkinson’s disease, women are more prone to mood disorders and Alzheimer’s disease.
The U.S. study, inScience, is the first systemic single-cell survey of sex differences in gene expression across multiple regions of the human brain.
“Together, these findings provide a comprehensive map of molecular sex differences in the human brain and offer initial insight into their underlying mechanisms and potential functional consequences,” Alex DeCasien, PhD, from the National Institute of Mental Health in Bethesda, Maryland, told Inside Precision Medicine.
DeCasien and co-workers conducted a high-resolution analysis of gene expression in tissue samples from the brains of 15 men and 15 women using single-nucleus RNA sequencing.
They then used data from earlier large neuroimaging studies to select six cortical regions to sample, four of which showed sex-related differences in grey matter volume and two in which no such differences were found.
The team found subtle but widespread differences in gene activity between men and women. Biological sex explained very little of the variance in gene expression across the brain, at less than 1%, but differences were widespread—with more than 3000 genes showing different expression according to sex in at least one cortical region.
The greatest sex-related differences in gene expression were on the sex chromosomes. However, most of the genes showing sex-related variations in expression were autosomal—carried on one of the 22 numbered non-sex chromosomes.
The predominant driver for sex-biased expression of genes on these autosomal chromosomes were sex steroid hormones such as estrogen and testosterone.
Surprisingly, more than half the X chromosome genes in women were expressed in both alleles for at least one cell type. This indicated that many had escaped X chromosome inactivation—a female phenomenon in which one of the two X chromosomes is switched off early in development to stop women producing double the number of X-linked gene products to men.
“That finding has implications for understanding sex-biased disease susceptibility because several genes implicated in neurodevelopmental disorders reside on the X chromosome,” commented Jessica Tollkuhn, PhD, from Cold Spring Harbor Laboratory, and S Marc Breedlove, from Michigan State University, in an accompanying Perspective article.
They noted that autosomal genes showing sex-biased expression were substantially enriched for extracellular matrix components, hormone signaling pathways, and metabolic processes. “Genes with greater expression in women were enriched for mitochondrial and synaptic functions, whereas male-biased genes were associated with metabolic and structural pathways,” the editorialists added.
“By pinpointing these sexually differentiated processes, the data provide a treasure trove for the discovery of biomarkers of and/or therapeutic targets for differential disease risk in men and women.”
DeCasien and team added: “These findings raise the possibility that sex differences in gene expression modulate the magnitude of genetic effects at risk loci, contributing to differences in disease vulnerability and to reduced portability of polygenic risk prediction across sexes.”
Though the placebo effect is a well documented phenomenon, the neurological mechanisms that underlie the process are still not fully understood. Now scientists from multiple institutions led by a team at the University of California San Diego (UCSD) have pinpointed the brain circuitry in mice that they believe is responsible for placebo pain relief. Details of their findings are published in a new paper in the journal Neuron. In it, they describe brain regions that support placebo effects and highlight sites where endogenous opioid neuropeptides send signals that are important for placebo pain relief.
The paper is titled “Top-down control of the descending pain modulatory system drives multimodal placebo analgesia.” According to the team, theirs is the first study to establish placebo mechanisms by adapting a protocol used for humans to work in mice. Working alongside labs at the University of Pennsylvania, University of California Irvine, and elsewhere, the UCSD team detected activity in parts of the mouse brain that correspond to those previously implicated in human studies. Furthermore, by precisely mapping neural pathways and brain activity in the mice, the team identified essential roles for neural circuits that link the cortex to the brainstem and spinal cord during placebo pain relief.
They also found that training mice to exhibit a placebo effect with one type of pain results in relief from several different types of pain including pain from injuries. That is particularly notable because it has “direct implications for how placebo training in humans might be used to produce resilience to future pain that results from injury,” explained Matthew Banghart, PhD, an associate professor in UCSD’s neurobiology department and lead author on the study. The findings also open a door to “expectancy-driven” placebo effects as a substitute for addictive painkillers, he noted, meaning that it might be possible to use placebo conditioning to train patients to build preemptive resilience to pain.
Full details of the findings and methods used are provided in the paper. In it, the teams explain that they used sensor technology and a light-activated drug developed in the Banghart lab to study the role of naturally-occurring opioid peptides in the brain. Specifically, they used the sensors to detect opioid peptide signaling in the ventrolateral periaqueductal gray (vlPAG) region, a known hub for pain signaling, during placebo trials. They then used the light-activated drug called photoactivatable naloxone, or PhNX, to establish that these opioid peptides actually drive pain relief in a manner similar to drugs like morphine. The light allowed the scientists control and timing of the opioid signaling interference. Using PhNX, they confirmed that both morphine-induced pain relief and placebo pain relief use the same opioid signaling pathway in the vlPAG region of the brain.
Essentially, “we trained a mouse brain to create its own broad-spectrum painkillers on demand, precisely where they are needed to treat pain, without the off-target effects of opioid-based painkillers,” said Janie Chang-Weinberg, a PhD student in the biological sciences graduate program at UCSD and one of the first authors on the study.
Future studies planned by the team will dig more deeply into how placebo learning unfolds in the brain and evaluate different placebo training strategies in mice with an eye towards developing protocols that readily translate to produce placebo pain resilience in people living with chronic pain.
Finnish deep-tech startup, Proteins.1, launched with €4.7 million in pre-seed funding, led by Lifeline Ventures and Cloudberry Ventures, with in-kind support from VTT and Business Finland. Harnessing technology transferred from VTT Technical Research Centre of Finland, Proteins.1 is developing a PCR-like enzyme-free, ultra-sensitive amplification platform for the detection of proteins at the single-molecule level. The firm says it aims to transform early disease diagnostics by enabling detection of disease-related molecular warning signals long before there are clinical signs.
While polymerase chain reaction (PCR) technology has transformed modern diagnostics by allowing tiny amounts of DNA to be amplified into detectable signals, no equivalent amplification method has existed for proteins, which often signal the earliest onset of cancer, neurodegeneration, cardiovascular disease, and inflammatory conditions, the company notes. Proteins.1 aims to leverage its technology to establish a new category of ultra-sensitive protein diagnostics, combining high multiplexing, scalable chip-based detection, and significantly lower capital costs compared to existing systems.
The patented, physics-based technology introduces cyclic signal amplification for proteins, potentially enabling up to 1,000 times better sensitivity than current gold-standard platforms, Proteins.1 claims. Unlike conventional immunoassays that rely on enzymatic reactions prone to variability and noise, the Proteins.1 approach is solid-state, enzyme-free, and compatible with semiconductor-based photonic detection.
The platform replaces enzymatic signal amplification with a physics-based magnetic cycling mechanism that repeatedly reads a single captured protein molecule, accumulating signal clarity without increasing background noise. The company says this supports ultra-high sensitivity combined with high multiplexing, potentially enabling the simultaneous measurement of hundreds of biomarkers from a few drops of blood.
“For decades, diagnostics has been limited not by biology, but by what our instruments can detect,” commented Proteins.1 co-founder and CEO Prateek Singh, who is inventor of the core technology. “The body produces early warning signals long before disease becomes visible. Our mission is to make those signals measurable and actionable, years earlier than today.”
Built on research conducted at VTT and further validated through European Union breakthrough innovation funding, the technology has been granted U.S. and Finnish patents, and additional international applications are pending. Initially, the company aims to develop research-use-only applications in oncology, neurology, and immunology, before progressing toward regulated clinical diagnostics. “Early detection dramatically improves survival rates in diseases such as cancer and neurodegenerative disorders,” Singh continued. “If we can detect disease at the molecular stage rather than the symptomatic stage, we entirely change treatment possibilities.”
Proteins.1 plans to expand its engineering and product development team in Finland during 2026–2027, positioning itself as a European hub for next-generation diagnostic technology. “Proteins.1 represents the kind of deep scientific breakthrough that can redefine an entire industry,” said Jyri Engeström at Lifeline Ventures. “The team combines world-class research with proven experience in building and scaling regulated medtech businesses.” Cloudberry Ventures further highlighted the company’s strong alignment with European strengths in photonics, microfabrication, and precision engineering.
Added Rene Kromhof, at Cloudberry VC, “What sets Proteins.1 apart is a fundamentally new sensing approach. Rather than using enzymes that give you one chance to detect a protein, they use light and thin-film transistors to amplify the signal from a single protein until it rises above the noise. That dramatically improves sensitivity, and ultimately, how early disease can be caught.”
CEO Prateek Singh has previously raised venture capital for microfluidics ventures and holds multiple patent families. Co-founder and COO Harri Hallila previously built and exited a regulated medical device company. The broader team includes commercial leadership with experience in leading diagnostics platforms.
The American Association for Cancer Research (AACR) Annual Meeting kicks off this weekend in San Diego. A whirlwind of sessions, keynotes, fireside chats, posters, and exhibitors, the meeting is THE annual event for the cancer community.
Before the conference, GEN spoke with AACR program chairs Paul S. Mischel, MD, Professor and Vice Chair for Research for the Department of Pathology at Stanford Medicine of Stanford University and Alice T. Shaw, MD, PhD, Chair of the Department of Medical Oncology and the Chief of Strategic Partnerships at Dana-Farber. In this interview, they share their perspectives on the event, what attendees should be looking out for, and what they, personally, are most looking forward to.
This interview has been edited for length and clarity.
GEN: What did you feel were some of the most important themes to include in the conference program?
Shaw: First of all, it’s been such an honor for me to work with Paul as well as our president, Lillian Siu, MD. We had an expert program committee and incredible staff at AACR who all helped shape the program.
This year’s annual meeting feels more meaningful than ever, because of everything going on in the world, including funding challenges, challenging geopolitics, and everything else. It has felt even more important that we have this time to bring together our global community of cancer researchers and investigators.
When Paul and I met last summer, we felt strongly that this meeting was not just about designing an incredibly strong scientific program to showcase the science and all of the innovation, but we wanted to make a point to demonstrate to the audience, and the world, the tangible benefits of scientific research to patients with cancer, and to highlight how all the research we do is done with an eye toward improving the lives of patients with cancer.
We intentionally planned a scientific program with patients and patient impact front and center and have tried to incorporate the patient perspective and even patient voices in some sessions—to emphasize that science drives impact for patients.
Mischel: When we started about a year ago, our conviction—that there probably has never been a more important year for an AACR meeting—grew over the year. This organization is a beacon of light at a time in which there’s been extraordinary progress in cancer, and [there is] the potential to really make a difference in patients’ lives at the face of some very major headwinds. What we’re seeing is a level of enthusiasm and engagement in coming together in the community that’s saying: we won’t be stopped in making a difference for patients with cancer. And there were a number of themes that were central to this meeting.
For example, precision—that you can use information about patients to identify what’s gone wrong and how to develop therapies based upon deep molecular knowledge. Partnership—The growing recognition of how we work together to make a difference for patients. It’s not a winner-take-all strategy. It’s not a race to the top for individuals. It’s a race to the top for people with cancer. And we do it effectively by joining hands to make a difference for patients. And global work—another major theme that we’re really talking about this year, because together we can make a real difference for people with cancer.
We work together with people that span an enormous range of disciplines and expertise. A number of themes came front and center during the year. The technologies to interrogate what’s happening in human beings, whether it’s in their tissue, their blood, or their images—it’s nothing short of breathtaking. The ability to either forestall cancer by detecting if it’s going to happen, or catch it early, or monitor our most effective treatments is really changing the game. New modalities for developing treatments. We’ve heard a lot about harnessing the immune system and about the development of small molecules. There’s all kinds of new chemistry, molecular glues and degraders that are leading the way. And they’re tied to deep investigations into the fundamental biology.
AI is changing the game as well. We are very excited that we’ve brought together perhaps the most interesting AI sessions that you can imagine, that talk about all of the ways that AI can be used—not like an oracle but actually in partnership with helping make a difference for patients, whether it be in the diagnostics or the development of therapeutics. AI is only beginning to be tapped to help us think about how to integrate knowledge across all of these domains. And it goes beyond that because it’s not only about the molecular composition of a person’s tumor, it’s about a human being, what they eat, where they live, what they do, and various other social determinants of health that might increase risks of cancer. A lot of attention is paid in the meeting to that aspect of it as well. So, I think we’re in for an incredibly interesting meeting.
Shaw: One of the themes that came right out from everyone on the program committee was how important it was to highlight AI; I think everyone believes that AI is going to be transformative and it’s going to impact all aspects of cancer research and clinical care in the coming years. We had a number of AI experts on our program committee. They really helped embed AI topics throughout the scientific and also the educational program.
In fact, when Paul and I were planning the opening plenary session, we really wanted one of the opening plenary speakers to be able to speak on AI. So, we have Regina Barzilay, PhD, from MIT, who’s going to speak on her work in the AI space, both in terms of drug discovery and all the way out to clinical applications. We also have an AI-focused plenary session all unto itself as well, to drive home the importance of AI tools and technologies. It is incredible how AI is already being used in terms of foundational discovery and in terms of real-world, clinical data mining and implementation. And Paul already mentioned genomics, precision medicine, biomarker discovery, histopathology, radiology, all of which are already being impacted by AI.
Mischel: One of the things that is perhaps most stunning is this idea that you might be able to prevent cancer. We already see real world examples of that with things like HPV vaccines. The work is advancing so quickly that it might be possible to build vaccines against [something] that might prevent people who are at high risk of developing cancer from getting those cancers. Our colleague and AACR President Lillian Siu, MD, has a presidential symposium focused on that. What I hope that we’re getting across is the real scale and power of the work that’s being presented and the way that it crosses so many disciplines at this meeting.
Shaw: We are going to have a large focus, as we usually do, on molecularly targeted therapies. We have several sessions on the basic research side, but also in the clinical trial sessions around targeting RAS. RAS, of course, is the most commonly mutated oncogene in human cancer and has been undruggable for decades.
In the last five to 10 years, we now finally have small molecule therapies that can target different RAS mutations. In fact, you may have just heard the news about a new RAS inhibitor, daraxonrasib from Revolution Medicines, and pivotal Phase III trial data in previously treated pancreatic cancer. This was an incredibly positive study, doubling overall survival. Not even knowing those results, though, we already had planned quite a lot around RAS.
In that context of precision therapies, I also want to mention that I’m excited about one of our discovery science plenaries on Saturday that is going to focus on minimal residual disease (MRD) in solid tumors. Here the question is, if we have such incredibly effective targeted therapies for oncogene-driven cancers like RAS, EGFR, and ALK, why aren’t we curing more patients who have these types of cancers? We believe that a lot of the reason is because we can’t eliminate every cancer cell. And if we could just understand what allows those residual cells to survive, perhaps we could eradicate those and then be on the road to curing patients who have advanced disease. So, this whole plenary will focus on the science around MRD and how that then leads to clinical applications as well.
Mischel: Fundamental science is deeply central to this process. We frame a lot of things in terms of what it means for patients’ lives. I think an important part of this meeting is also integrating how those discoveries really flow from the work in fundamental science. For example, in the opening plenary, we’re going to be hearing about how tumors change their stripes effectively to become resistant to treatments, the lineage plasticity, this idea that they adopt new states to become resistant. And then what can you do about it?
When people used to be diagnosed with terminal cancer, it meant that they were going to die soon, and now people can be diagnosed with terminal cancer and live for years. That’s stunning. And that is happening because of cancer research and the integration of cancer research all the way from the most mechanistic to the most applied. One of the deepest themes of this meeting comes into this concept of partnership, that we highlight the critical nature of each component and the integration of those components, all the way from fundamental discovery to translation to patients.
GEN: What are some of the biggest scientific challenges you’re seeing right now in cancer biology that you think people will be discussing at the meeting?
Mischel: Cancer is hard because it is evolution on steroids. The mechanism that I study—extrachromosomal DNA, the ability of cancer cells and tumors to change quickly to resist treatment—is all about that. And it comes from us; it’s our cells that have gone bad. We have to find ways to show how they’re different and target those differences. We’re getting better at it through our understanding of science.
Shaw: I am someone who sits between basic research and the clinic, so I do a lot of translational research. What the AACR meeting does well is gets at this key challenge around how we translate basic discoveries into the clinic. We all just want better cancer therapies for our patients. There are many aspects that really make the translation of discoveries difficult, and these will come out in various forms at the meeting. We’ve been talking about how hard it is to understand the biology, and to identify and validate new targets for drug discovery, for cancer treatments in the future.
I have spent some time on the industry side, so I also recognize how challenging it is, even when you have what you think is a perfect target, to drug that target. At the annual meeting, we’re going to talk a lot about different modalities, ways of thinking about going after what we believe are important targets, be it a small molecule or maybe it’s a new degrader or maybe it’s some other very complicated biologic.
I want to emphasize that to use or to identify the optimal modality requires that we understand the biology and the science behind it. The other challenge that I’ve seen in the translational space is around identifying which patients are going to benefit from a new therapy. A good example of where we’ve seen struggles is immunotherapy and identifying novel immunotherapy combinations and which ones have robust activity. But we can’t tell exactly which patients are deriving that benefit. Oftentimes with no biomarker to guide us, we can’t move forward with what could be a promising combination. At the annual meeting, we try to highlight a lot of these correlative or translational biomarker studies from early phase clinical trials.
The last thing I’ll mention is around how we use preclinical models most effectively to predict what’s going to be a promising new therapy. Often, these models are just models; they’re simpler than human cancers. They can’t recapitulate the complexity of human biology, and they can lead us the wrong way. For example, to overestimate how effective a therapy may be. Fine-tuning our models and making them as predictive as possible is a key challenge.
Mischel: Data seems to suggest that very often you might need to combine agents to make differences for patients. And that of course makes enormous sense from a biological standpoint, but it’s much harder to do when you start thinking about how you design the trials to do that. It’s a slow process. And so, there is increasing recognition of the need to figure out how to combine agents and hopefully ways to figure out how practically to begin to test them more effectively and in a more cost-effective fashion.
GEN: What have been some of the biggest advances since the last meeting?
Mischel: I just keep coming back to RAS because it’s such a big deal. An undruggable target that we’re now seeing a huge change in. It’s a huge deal.
Shaw: I would agree with that. And it’s not simply the RAS inhibitor itself. Many of us believe that that is just the start of how we most effectively treat RAS-driven cancers. We need the best RAS inhibitor to serve as an anchor and then we will build these combinations around that which will hopefully be even more effective and allow us to maximally cytoreduce or debulk cancers and then allow us to take in other even higher order combinations.
We have sessions this year all around RAS-mutant cancers. We have a designated session just focused on pancreatic cancer biology, because understanding that biology well is going to be critical to developing these types of combination approaches.
The other thing that’s exciting—and this space is always evolving—is a plenary session on innovative new therapeutic modalities. This session will focus on a couple key modalities that are already transforming the space. Antibody-drug conjugates (ADC), for example. They are basically entering every therapeutic space that we have in cancer [and] understanding of the biology around how you’re targeting certain tumor-selective antigens.
Also, the design of the ADC itself can be very, very sophisticated and can be tweaked to further enhance activity. We’ll have some great talks around the next generation of ADCs that are going to be even more effective and even safer than what we currently have.
And in that same session around innovative modalities, we’ll also have talks around immune cell engagers; also, new data and next generation immune cell engagers that have built upon the early data with the first-generation immune cell engagers. The other very innovative new therapy that we will highlight, even in more detail than last year, is around radioligand therapies—a way to selectively target tumor cells with radiation. Unlike ADCs where the payload is chemotherapy, here the payload is radiation therapy. We’ve already seen really that these radioligand therapies are incredibly important for patients; they are coming out in all different therapeutic spaces. We thought it was important to highlight the latest advances in radioligand therapies, and we also have some education sessions so that physicians and scientists understand the basics around this innovative and exciting modality.
Mischel: The concepts of glues and degraders open the therapeutic landscape in a very different way. In many ways, the landscape has been limited to enzymes that you can inhibit, and not all good cancer targets are going to be enzymes that you can inhibit, and these glues and degraders change what you can do, whether it’s getting rid of them, moving them, giving them new functions. It’s a very powerful technology that is getting ready to make an enormous difference in clinic.
Shaw: In the opening plenary session, George Winter will speak on glues and degraders. I also wanted to highlight the “New Drugs on the Horizon” sessions. We do this every year at the annual meeting. I love these sessions because they are first time disclosures of novel cancer therapies that have just entered the clinic or they’re about to enter the clinic. These talks go deep into the biology of the disease and how the drug was discovered and developed into early clinical plans. Several talks in this session this year are going to feature molecular glue degraders. That will be a nice way to tie together this theme around the degraders and the power of this new modality.
Mischel: One other thing I want to squeeze in is why on Earth are younger people getting cancer, particularly colorectal cancer? That’s really disturbing. We have sessions that are data rich that go right at that, and the answers are interesting.
GEN: Will there be any programming at the meeting that addresses the current state of funding?
Shaw: We’re fortunate that Tony Letai, MD, PhD, the NCI director, is attending and speaking at the meeting in our opening ceremony on Sunday. He’s also participating in a workshop that we’re holding on grant writing and the scientific review process. On Monday, he will give an NCI director’s address and participate in a fireside chat where I’m sure he’s going to get a lot of questions around funding.
There are also sessions within the science and health policy track at the meeting that are going to focus on federal funding of grants. There is even a researcher town hall that’s really going to talk a lot about this.
GEN: Do you have any advice for young cancer researchers that may be attending AACR for the first time?
Mischel: I have two bits of advice. One of them is to know that what you’re doing is incredibly important. You are welcome. You’re one of us, you’re important. Do what you need and go forward because the work that you’re doing is going to matter an enormous amount. The second thing is do not be afraid. Do not think that the senior people at the meeting, the “bigwigs,” are too busy for you. Do not think they do not want to meet you, because they do. You’re the future. Go up, introduce yourself, say hello, tell us who you are.
GEN: What are things you are looking forward to outside of the sessions?
Shaw: I love the AACR annual meeting because it’s such an opportunity not just to learn, but to network and reconnect with friends and collaborators who you may not have seen in a while. I also think it’s a great venue for many of us to have formal sit-down meetings with industry partners and talk through the latest data that were just presented and discuss new collaborations. I personally am looking forward to the 5K race that Paul and I are speaking at. I’m going to try to run the race! One of my sons runs marathons and I thought, well, the least I can do is try and run a 5K.
Mischel: I’m looking forward to having a drink with Alice after the meeting ends and debriefing on putting this meeting together, which has been an absolute pleasure. I wish I were running the 5K race. I’m doing an education session at that time. I’m looking forward to meeting the students. There are these brilliant young people from all around the world and they’re just at the start of their career and they draw inspiration from this meeting, and I really enjoy it when they come up to me and I get to meet them. You see the brilliance and excitement in these people’s faces. And I’m looking forward to that.
Invivoscribe launched the PrepQuant sample preparation platform that integrates nucleic acid extraction, concentration, and quantification with a single automated instrument. The product is designed to standardize sample preparation and simplify pre-analytical workflows to reduce costs and eliminate a primary source of inconsistency in molecular testing.
Developed in collaboration with Hitachi High-Tech Corporation, PrepQuant combines Invivoscribe’s experience in developing standardized molecular assays, providing global clinical testing services, along with Hitachi High-Tech’s technological and manufacturing capabilities
The PrepQuant system is assay agnostic, generating highly concentrated genomic DNA and cell free DNA (cfDNA) yields for next-generation sequencing (NGS), qPCR, and digital PCR (dPCR) assays. By consolidating multiple steps in a single platform, the system can lab operating costs, sample variability, and lab bench space, while optimizing tests results.
“PrepQuant represents a significant advancement in our commitment to standardize the entire testing process, starting with the pre-analytical workflow,” said Jeff Miller, CEO and CSO of Invivoscribe. “This is particularly important in the era of precision medicine, where reliability of measurable residual disease and liquid biopsy results depend markedly on the quality and consistency of the starting material.”
“The concept for the [product] was driven directly by insights from LabPMM, our global network of testing laboratories,” added Jordan Thornes, vice president, global clinical lab operations. “Our teams recognized the limitations of currently available automated instruments, particularly the labor-intensive nature and increased risk of errors associated with running three separate protocols across multiple instruments. This all-in-one system was designed to reduce costs, while addressing those challenges and significantly improving operational efficiency.”
The PrepQuant is designed and validated for use with blood, plasma, and bone marrow specimens, with ongoing development for additional specimen types. Invivoscribe will officially unveil the product at the American Association for Cancer Research (AACR) Annual Meeting in San Diego, at booth #3459 from April 19–22.
Earlier this week, Revolution Medicines reported positive results from a global Phase III trial of its RAS‑targeting inhibitor daraxonrasib (RMC-6236) in metastatic pancreatic ductal adenocarcinoma (PDAC). In the RASolute 302 trial, patients receiving daraxonrasib achieved longer progression‑free survival (PFS) and overall survival (OS) than those on standard cytotoxic chemotherapy.
The RASolute 302 trial enrolled patients with pancreatic tumors harboring a wide range of RAS variants, including those with RAS G12 mutations (such as G12D, G12V, and G12R), as well as those without an identified RAS mutation. The primary endpoints of the trial were PFS and OS in patients with tumors harboring RAS G12 mutations. Secondary endpoints assessed PFS and OS in all enrolled patients (the intent-to-treat population), including those with tumors with and without (wild type) an identified RAS mutation.
Daraxonrasib patients achieved a median OS of 13.2 months versus 6.7 months for chemotherapy. The drug was generally well tolerated, with a manageable safety profile and with no new safety signals.
“With these unprecedented results, daraxonrasib has the potential to achieve our goal of bending the mortality curve in pancreatic cancer. Unlike chemotherapy, daraxonrasib is a RAS-targeted medicine that targets RAS in its active ‘ON’ state, shutting down a key signaling pathway that drives aggressive tumor growth. This is especially important in pancreatic cancer, which is among the most RAS-driven cancers, with more than 90% of tumors harboring a RAS mutation that is the driver of the cancer,” asserted Mark A. Goldsmith, MD, PhD, CEO and chairman of Revolution Medicines.
Pancreatic cancer carries one of the highest mortality rates of any solid tumor, a consequence of late-stage diagnosis and resistance to standard chemotherapy. In the United States, recent estimates point to roughly 60,000 new cases and nearly 50,000 deaths each year. With most PDAC tumors driven by RAS alterations, the early success of emerging RAS‑targeted strategies hints at how much more may be possible as this therapeutic space continues to expand.
RAS is the key oncogenic driver of pancreatic cancer. Nearly all RAS mutations occur at KRAS position G12, but RAS mutations in other isoforms and at KRAS positions G13 and Q61 are also observed. Daraxonrasib works by suppressing RAS signaling through inhibition of the interaction between both wild-type and mutant RAS(ON) proteins and their downstream effectors.
Pancreatic cancer is the most RAS-addicted of all major cancers, with more than 90% of patients harboring tumors driven by mutations in RAS proteins. These mutations span a range of RAS variants that fuel aggressive tumor behavior. Daraxonrasib, a multi-selective inhibitor of RAS(ON) proteins, is the first investigational agent in a novel class of RAS inhibitors designed to address a diverse and broad spectrum of oncogenic RAS drivers.
“For patients with metastatic pancreatic cancer, new treatment options are urgently needed to increase survival time and improve quality of life,” said Brian M. Wolpin, MD, MPH, professor of medicine at Harvard Medical School, director of the Hale Family Center for Pancreatic Cancer Research at Dana-Farber Cancer Institute, and principal investigator for the RASolute 302 trial. “The widely anticipated results of this study indicate that daraxonrasib provides a clear and highly meaningful step forward for patients with pancreatic cancer who have experienced progression on prior treatment, typically chemotherapy. I believe that this new approach is a very important advance for the field that I expect will be practice-changing for physicians and improve the care for patients with previously treated metastatic pancreatic cancer.”
Revolution Medicines now intends to submit the drug for approval by regulatory authorities, including the U.S. Food and Drug Administration as part of a future New Drug Application, and for presentation at the 2026 American Society of Clinical Oncology Annual Meeting.
Health disparities in the United States are not produced by single risk factors but by interacting social and biological conditions that cluster within structurally marginalized communities. Poverty, violence, and poor physical and mental health form a reinforcing system of disadvantage that traditional healthcare models—organized around isolated diseases—are poorly equipped to address. This perspective examines these dynamics through a syndemic framework, which conceptualizes co-occurring conditions as mutually interacting epidemics intensified by social inequality. Drawing on interdisciplinary evidence from public health, medicine, and social science, we describe how poverty-related stressors such as housing instability, food insecurity, and barriers to healthcare intersect with exposure to interpersonal and structural violence to amplify risks for depression, posttraumatic stress disorder, chronic disease, and premature mortality. These interactions produce compounded health burdens that are disproportionately experienced by marginalized populations. Despite increasing attention to social determinants of health, current healthcare responses remain fragmented. Health systems frequently identify risks through screening for social needs or trauma exposure but lack the institutional infrastructure, reimbursement mechanisms, and cross-sector partnerships required to address them effectively. We argue that advancing health equity requires moving beyond additive models of care coordination toward syndemic-informed healthcare systems that intervene simultaneously on clustered conditions and their shared upstream drivers. We outline key priorities for practice, policy, and research, including linking screening to actionable care pathways, strengthening partnerships between healthcare and social service systems, and expanding workforce training to include structural and syndemic competency.
In an attempt to win European approval for the controversial medicine, Roche said Thursday it would run another trial of the Duchenne muscular dystrophy gene therapy Elevidys.
The Swiss company’s move comes after European regulators last year gave a negative review to the therapy, saying it had failed to demonstrate long-term benefits for patients with the degenerative muscle condition. Roche has rights to the therapy outside the U.S., where it is marketed by its developer, Sarepta Therapeutics.
Roche said the Phase 3 trial will generate the type of evidence that could lead to a resubmission with European officials and to applications with regulatory agencies in other parts of the world. The study will evaluate the safety and efficacy of Elevidys versus placebo over 72 weeks in roughly 100 boys at the early stages of the disease.
Last week, news outlets reported that Microsoft was pausing carbon removal purchases. It was something of a bombshell.
The thing is, Microsoft is the carbon removal market. The company has single-handedly purchased something like 80% of all contracted carbon removal. If you’re looking for someone to pay you to suck carbon dioxide out of the atmosphere, Microsoft is probably who you’re after.
The company has said that it is not permanently ending its carbon removal purchases (though it didn’t directly answer further questions about this apparent pause). But with this flurry of news, there’s a lot of fear in the industry—so, it’s worth talking about the state of carbon removal, and where Big Tech companies fit in.
Carbon removal aims to reliably pull carbon dioxide out of the atmosphere and permanently store it. There’s a wide range of technologies in this space, including direct air capture (DAC) plants, which usually use some kind of sorbent or solvent to pull carbon dioxide from the air. Another important method is bioenergy with carbon capture and storage (BECCS), in which biomass like trees or waste-derived biofuels are burned for energy, and scrubbing equipment captures the greenhouse gases.
There was a huge boom of interest in carbon removal technologies in the first half of this decade. One UN climate report in 2022 found that nations may need to remove up to 11 billion metric tons of carbon dioxide every year by 2050 to keep warming to 2 °C above preindustrial levels.
One nagging problem is that the economics here have always been tricky. There’s a major potential public good to pulling carbon pollution out of the atmosphere. The question is, Who will pay for it?
So far, the answer has been Microsoft. The company is by far the largest buyer of carbon removal contracts, and it’s the only purchaser that has made megatonne-scale purchases, says Robert Höglund, cofounder of CDR.fyi, a public-benefit corporation that analyzes the carbon removal sector. “Microsoft has had a huge importance, especially for getting large-scale projects off the ground and showing there is demand for large deals,” Höglund said via email.
Microsoft has pledged to become carbon-negative by 2030 and to remove the equivalent of its historic emissions by 2050. Progress on actually cutting emissions has been tough to achieve though—in the company’s latest Environmental Sustainability Report, published in June 2025, it announced emissions had risen by 23.4% since 2020.
On April 10, Heatmap News reported that Microsoft staff had told suppliers and partners that it was pausing future purchases of carbon removal, though it wasn’t clear whether the company would increase support for existing projects, or when purchases might resume. Bloomberg reported a similar story the next day. In one instance, Microsoft employees said that the decision was related to financial considerations, one source told Bloomberg.
In a statement in response to written questions, Microsoft said that it was not permanently closing its carbon removal program. “At times we may adjust the pace or volume of our carbon removal procurement as we continue to refine our approach toward sustainability goals. Any adjustments we make are part of our disciplined approach—not a change in ambition,” Microsoft Chief Sustainability Officer Melanie Nakagawa said in the statement.
Whatever, exactly, is happening behind the scenes, many in the industry are nervous, says Wil Burns, Co-Director of the Institute for Responsible Carbon Removal at American University. People viewed the company as the foundational supporter of carbon removal, he adds.
“This pause—whether it’s short term or whatever it is—the way it’s been rolled out is extremely irresponsible,” Burns says. The vast majority of firms looking to get carbon removal contracts are probably seeking Microsoft deals. So, while Microsoft has every right to change its plans, the company needs to be open with the industry now, he adds.
“I don’t think you can hold yourself out as the paragon of fostering carbon removal and then treat a nascent industry that disrespectfully,” Burns says.
Carbon removal companies were already in turmoil in the US, particularly because of recent policy shifts: Funding has been cut back, and recent changes at the Environmental Protection Agency were aimed at the government’s ability to target carbon pollution.
Now, if the largest corporate backer is shifting plans or taking a significant pause, things could get rocky.
Depending on the extent of this pause, the industry may need to survive on smaller purchases and hope for support from governments and philanthropy, Höglund says. But for carbon removal to truly scale, we need policymakers to create mandates so that emitters are responsible for either storing the carbon dioxide they produce or paying for it, Burns says.
“Maybe the upside of this is Microsoft has sent a wake-up call, that you just can’t rely on the kindness of strangers to make carbon removal scale.”
This article is from The Spark, MIT Technology Review’s weekly climate newsletter. To receive it in your inbox every Wednesday, sign up here.
When the covid-19 pandemic started, Jennifer Phillips thought about the songs of the sparrows.
They were easier to hear, because the world had suddenly become quieter. Car traffic plummeted as people sheltered at home and shifted to remote work. Air travel collapsed. Cities—normally filled with the honking, screeching, engine-gunning riot of transportation—became as silent as tombs.
For years, Phillips has studied how animals react to “anthropogenic noise,” or the racket created by human activity. Most animals really don’t like it, she and her colleagues have learned. Animals constantly listen to the world around them: They’re on the alert for the rustle of approaching predators, or a mating call from a member of their species. As human society has expanded—with sprawling cities, industrial mines, and roads crisscrossing the world—it has gotten noisier too, and animals have trouble hearing one another.
Noise is invisible; there’s no billowing smokestack, no soiled waterway. We just got used to it as it vibrated in the background.
Phillips and her colleagues had spent time in the 2010s in San Francisco recording the sound of white-crowned sparrows in the Presidio. It’s a park that is half peaceful nature and half automobile noise, since it’s filled with thick clumps of trees and grassy fields but also has two highways that slice through it, feeding onto the Golden Gate Bridge. In past recordings, starting in the 1950s, sparrows had sung with complex and lower-pitched melodies and three major “dialects.” But by the 2010s, traffic in the Presidio had exploded, and the hubbub was so loud that the birds began to sing with faster trills—and at a higher pitch—so their fellows could hear them. The two quietest dialects were either dead or on their way to extinction.
They’re “screaming at the top of their lungs,” says Phillips. “They really can’t hear the lower frequencies when the traffic noise is present.” Urban noise can even change birds’ bodies; they get thinner and more stressed out. Their mating calls aren’t as effective, because female birds, as researchers have found, generally don’t enjoy high-pitched, high-volume shouting. (It makes them wonder if the males are unhealthy.) The noise can increase bird-on-bird conflict, because when birds can’t hear warning cries they accidentally stumble into enemy territory. Perhaps worst of all, in situations like these biodiversity takes a hit: Entire species that can’t handle urban clamor simply head out of town and never come back.
But as the sudden, eerie silence of the pandemic descended, Phillips sat at home thinking, It’s really quiet. And then she wondered: Would the Presidio birds now be able to hear each other better?
She raced over to the park and started recording. Sure enough, the park was seven decibels quieter—a huge drop. (That’s like the difference between the noise of the average home and whispering.)
And remarkably, the researchers found that the songs of the white-crowned sparrows had transformed. They were singing more quietly, with a richer range of frequencies. A bird could be heard twice as far as before. And the mating calls had gotten more sultry.
“They could sing a higher performance, basically a sexier song, but not have to scream it so loud,” Phillips says.
It was as if time had been reversed and all the damage abruptly repaired. And it proved what Phillips and her peers have been increasingly documenting: that anthropogenic noise is the newest form of pollution we need to tackle. The noise of our relentlessly on-the-move industrial society affects all life on Earth, wildlife and humans, in ways we’re just beginning to grasp. Yet strategies such as electrification and clever urban design could help. As the Presidio showed, noise can vanish overnight—once we figure out how to shut up.
Hidden impacts
Many forms of pollution are obvious to us humans. Dumping toxic goo into lakes? Sure, that’s bad. Coal smokestacks pumping soot and carbon dioxide, plastic bags and sea nets choking whales—we now understand that these, too, are problems. Even an idea as gauzy as light pollution has penetrated the public consciousness to some extent, since it’s why city dwellers can’t see many stars, and we’ve heard it confuses migratory birds.
But noise, mostly from transportation, took longer to hit our radar. This is partly because it’s invisible; there’s no billowing smokestack, no soiled waterway. We just got used to it as it vibrated in the background.
Sparrows in San Francisco’s Presidio began to sing with faster trills—and at a higher pitch—so their fellows could hear them over the noise of nearby traffic.
GETTY IMAGES
The black-chinned hummingbird seems to prefer noisy areas, fledging more chicks than the same species does in quieter areas.
MDF/WIKIMEDIA COMMONS
There were a few studies in the ’70s and ’80s showing that animals were upset by our noise. But the field really began to take off in the ’00s, in part because digital technology made it easier to record long swathes of sound out in nature and analyze them. One early salvo came from the biologist Hans Slabbekoorn, who was studying doves in the city of Leiden and irritatedly noticed that he could rarely get a clean recording because of the background noise. Sometimes he’d see the doves’ throats moving as they cooed but couldn’t hear them. “If I’m having difficulty hearing them,” he thought, “what about them?”
So he and a colleague started recording ambient sound levels in different parts of Leiden. Some were quiet residential areas, which registered a soothing 42 decibels, and others were noisy intersections or areas near highways, which reached 63 decibels, about as loud as background music. Sure enough, he found that birds in the noisy areas were singing at a higher pitch.
Over the next two decades, research in the field bloomed. Noise, the scientists found, has a few common ill effects on animals. It disrupts communication, certainly. But it also generally stresses them, reducing everything from their body weight to their receptivity to mating calls. If an animal nests closer to a road, its reproduction rates can go down; eastern bluebirds, for example, produce fewer fledglings. Truly cacophonous noise—like planes taking off at a nearby airport—can cause hearing loss in birds. And animals can wind up becoming less aware of threats from predators. They’ll wander closer to danger, because they can’t hear it coming. (And sometimes they’ll do the opposite: They’ll develop a rageaholic hair-trigger temper, because they’re constantly on high alert and regard everything as a threat.)
Even in deep rural areas, where things are normally pretty quiet, highways can disrupt wildlife—the noise carries far into the fields nearby. Fraser Shilling, a biologist at the University of California, Davis, has stood up to half a mile from rural highways and recorded sound as loud as 60 decibels, which is at least 20 decibels higher than you’d typically find in the wilderness. “The motorcycles and the 18-wheelers are really the ones that project a lot of noise,” he told me.
Above 55 decibels, many skittish animals get into a fight-or-flight panic. The prevalence of bobcats—an endangered species famously rattled by noise—“starts dropping off the cliff,” says Shilling. Above 65, “you’re really starting to exclude almost all wildlife.”
And that’s not even the upper limit of what wildlife is exposed to. There are roughly a half-million natural-gas wells around the US, and piercingly loud compressors are used to shoot water down into most of them. Up close, the compressors can kick out 95 decibels, a sound as loud as a subway train; at one Wyoming gas well the sound still registered around 48 decibels nearly a quarter-mile away.
Historically, it wasn’t always easy to prove that noise was causing whatever problems the animals were experiencing. Maybe it was other factors; maybe animal populations reduce near a road because some are hit by vehicles?
But several clever experiments have proved that noise—and noise alone—can disrupt wildlife. One was the “phantom road” experiment by the conservation scientist Jesse Barber and his team, then at Boise State University. They went out to a quiet, uninhabited area of the Boise foothills in Idaho, far away from any roads. In this valley in the mountains, thousands of migratory birds stop on their way south each year; they’ll gorge themselves on cherry bushes, gaining weight for the next days of flying. The researchers strapped 15 pairs of speakers to Douglas fir trees, in a half-kilometer line. Then they blasted recordings of highway noise. They played the noise for four days and then turned it off for four days. Then they observed thousands of birds, capturing many to measure their body mass.
The noise truly rattled the birds. When the sound was turned on, nearly a third left the area. Those that stuck around ate less: While birds should be heavier after a day of foraging, these ones didn’t gain much. The noise seemed to have so interrupted their feeding that they weren’t packing on the weight needed for their migratory trip.
Other, similarly nifty A/B tests followed. One was led by David Luther, a biologist at George Mason University (who also worked with Phillips on the covid-19 study in San Francisco). In 2015, these researchers took 17 white-crowned sparrows at birth and raised them in a lab. To teach them their species’ songs, they played the nestlings recordings of adult sparrows singing, at low and high pitches. Six of the nestlings heard the songs without any interference; with the other half, the researchers played the sounds of city noise at the same time.
The results were stark. The lucky birds that were spared the traffic noise learned to perform the quieter, sweeter, more complex songs. But the birds that had traffic noise blasted learned only the higher, faster, more stressed-out songs. From the cradle, noise changed the way they communicated.
Humans hate noise too
You can’t pull the same experiment with humans, raising them in a lab to see how noise affects them. (Not ethically, anyway.) But if we could, we’d likely find the same thing. We, too, are animals—and it appears that we suffer in similar ways from anthropogenic noise, even though we’re the ones creating it.
The sound of traffic is correlated with lousy sleep, higher blood pressure, more heart disease, and higher stress.
Stacks of research in the last few decades have found that noise—most often, as with wildlife, the sound of traffic—is correlated with lousy sleep, higher blood pressure, more heart disease, and higher stress. A Danish study followed almost 25,000 nurses for years and found that an additional 10 decibels hit them hard; over a 23-year period they had an 8% higher rate of death, plus higher rates of nearly every bad thing that could happen to you: cancers, psychiatric problems, strokes. (They controlled for other malign health influences.) As you’d probably predict by now, children fare badly too. When Barcelona researchers followed almost 3,000 elementary school kids for a year, they found that those in noisier schools performed worse on assessments of working memory and ability to pay attention.
“We think of ourselves as being ‘used to it,’” says Gail Patricelli, a professor of evolution and ecology at the University of California, Davis. “We’re not as used to it as we think we are.”
It’s also true that there’s a trade-off. Many people understand that noise from cities and highways is aggravating, but we tolerate it because we get benefits along with the hassles. Cities are crammed with jobs and connections and dating opportunities; cars and trucks bring us the things we need and increase our personal mobility.
It turns out that animals make a similar calculus. Some species appear to benefit in certain ways from proximity to noise, so they move toward it.
Clinton Francis, a biologist at California Polytechnic State University, and a team studied bird populations near noisy gas wells in rural New Mexico. Most species avoided the riot of the well pumps. But Francis was surprised to find that some hummingbirds and finches preferred it, and by one important measure they thrived: They were nesting more in the noisy areas than in the quieter areas. Additionally, several species had more success at fledging chicks in noisier locations.
What was going on? It’s likely that the noise makes it harder for predators to hear the birds and hunt down their nests. “It’s essentially a predator shield,” Francis says. Since his research found that predators can cause as much as 76% of failures of eggs to produce healthy offspring, that’s a significant survival advantage.
Cities can offer the same protections to certain species. Consider the case of Flaco, a Eurasian eagle-owl that escaped from the Central Park Zoo in February of 2023 and found he was in a terrific place to hunt. The incessant traffic ought to have caused him trouble. “An owl like this is among the most vulnerable species to intrusions from noise pollution. They’re listening for extremely faint signals or cues that their prey provide,” Francis notes. But New York has its compensations, because prey animals abound. They’re also naïve and unguarded, never expecting an owl with a six-foot wingspan to swoop down and devour them.
EDDIE GUY
Granted, these upsides don’t cancel out the negatives. Human noise may shield some birds from predators, but in other ways it leaves them faintly miserable, with high levels of stress hormones and lower weight.
Worse, the species that manage to thrive in cities or near highways are often the same ones all over the country. And they represent only a minority of species; most are driven further away, with less and less land to live on as civilization spreads ever outward.
“Overall, it’s kind of a nightmare for diversity,” says Luther.
How to silence the world
In the early ’00s, the village of Alverna in the Netherlands began to get louder. A major intercity road cut straight through the town, and traffic had gone up by two-thirds in the previous decade. Facing complaints about the din, the town offered to put up some 13-foot walls on either side of the route. Residents hated the idea. Who wants to look out the window at massive walls?
So instead town planners redesigned the road in subtle ways. They lowered it by half a meter, slightly blocking the tire sounds. They built wedges that rise up three feet on either side, and surfaced them with attractive antique stone; that blocked even more sound. They planted sound-absorbing trees. And as a final coup de grâce, they reduced the speed limit from about 50 to 30 miles per hour. When a car is moving slowly, the engine is producing most of the roar—but once it’s going 45 mph or faster, the rumble of tires on the pavement takes over and is much louder. Each intervention had only a small effect, but cumulatively they made the road a blessed 10 decibels quieter.
This tale illustrates one curious upside of noise. Compared with other forms of pollution, it can be ended quickly. Toxic pollutants or CO2 can hang around for tens of thousands of years; the microplastics in your pancreas are probably never coming out. But with noise, the instant you reduce the source, the benefits are immediate.
Plus, most of what works is “not rocket science,” Shilling says. A tall wall at the side of a highway will cut noise by 10 decibels; fill a double-sided wall with rubble and it’s even better. That could cut the traffic noise to below 55 decibels, he notes, which would help particularly skittish forms of wildlife. Walls can block animal movement, though, so in animal-heavy areas it’s better to build berms—small hills on either side of a highway. Areas of high ecological importance could be prioritized to keep costs down.
“If there’s a great chunk of wetland habitat and it’s the only one around for 50 miles in any direction? Well, then we should build noise walls around it,” he says. We should also build overpasses and underpasses to help animals get around. And to quiet the din of gas wells out in the countryside, states could require companies to build walls around them. (They’ll likely only do that, though, when human neighbors complain or launch lawsuits; animals don’t have lawyers.)
Cities, too, can learn to shut up, as Alverna proved. At the most ambitious, some have buried noisy highways that once cut through the downtown core. Boston put a massive elevated highway underground in its “Big Dig”; in Slabbekoorn’s hometown of Amstelveen—a suburb of Amsterdam—they’re currently enclosing the A9 highway in a tunnel and turning the surface into a verdant park with new buildings. “That’s amazing, getting back a lot of the space as well,” he says.
Granted, this sort of reengineering can be brutally expensive, which is why politicians blanch when they’re asked to reduce road noise. The Big Dig cost $15 billion, and with interest up to $24 billion. When I mentioned cost to Shilling, he sighed. “It’s not as expensive as a B-1 bomber or tax cuts for rich people,” he says. “Environmental stuff is considered expensive just because our expectations are low, not because we can’t afford to do it.”
There are cheaper and more politically palatable fixes, though. Reducing urban speed limits is one; Paris recently cut the top speed on its ring roads from 70 to 50 kilometers per hour (43 to 31 mph), and noise at night went down by an average 2.7 decibels—a noticeable drop. Planting more trees and vegetation all around roads and cities can cut a few decibels more, and residents love it.
Growing adoption of electricity would also bring down the volume. “Electric vehicles of all kinds have the potential to make a big difference,” Patricelli says; when the light turns green and an EV next to you accelerates away, it’s up to 13 decibels quieter than a comparable gas-powered vehicle. These benefits won’t be felt as much on highways, because EVs still make tire noise at high speeds. But in the slower stop-and-go traffic of urban life, they are far more pleasant to the ears, both animal and human. Indeed, the electrification of everything that currently uses a gas-powered motor will make urban life quieter. Cities like Alameda, California, and Alexandria, Virginia, are increasingly banning gas-powered leaf blowers and lawn mowers, which operate at hair-raising volume while electric ones whisper along.
We’ve engineered a civilization that roars, but the next phase is making it purr. The animals will thank us.
Clive Thompson is a science and technology journalist based in New York City.
sample preparation platform that integrates nucleic acid extraction, concentration, and quantification with a single automated instrument. The product is designed to standardize sample preparation and simplify pre-analytical workflows to reduce costs and eliminate a primary source of inconsistency in molecular testing.
