STAT+: New data may cast doubt on competitiveness of Boehringer’s obesity drug

New data on Boehringer Ingelheim’s obesity candidate suggest the drug may be helpful in cutting liver fat, but it’s not clear how competitive the treatment would be since it appears less efficacious and less tolerable than drugs on the market.

In a Phase 3 obesity trial, patients on the highest dose of the weekly injectable, called survodutide, lost 13% of their weight after 76 weeks, compared with 5% in the placebo group, according to data presented Sunday at the annual meeting of the American Diabetes Association and published in the New England Journal of Medicine. That’s lower than the rate of weight loss seen in pivotal trials of Novo Nordisk’s Wegovy and Eli Lilly’s Zepbound. 

Patients on survodutide, which targets the GLP-1 and glucagon hormones, did lose up to 63% of their liver fat, compared with 25% in the placebo group. Glucagon-targeting drugs are thought to be particularly helpful in cutting liver fat, since there are glucagon receptors in the liver.

Continue to STAT+ to read the full story…

Blood-Based Risk Score Could Enable Earlier Lung Cancer Prevention

Researchers have identified a 14-protein blood signature capable of predicting lung cancer risk more than five years before diagnosis, potentially opening the door to a new era of precision cancer prevention.

The study, published in Cell by investigators at The Francis Crick Institute and University College London (UCL), combines large-scale human population data, mechanistic laboratory studies, and clinical trial analyses to demonstrate that a blood-based inflammatory signature can identify individuals at elevated risk of lung cancer and may pinpoint those most likely to benefit from preventive treatment.

The findings move beyond traditional risk models based on age and smoking history and offer what researchers describe as a potential equivalent of cholesterol testing for lung cancer prevention.

Moving beyond smoking-based risk assessment

Current lung cancer screening programs primarily target older individuals with a history of smoking. While smoking remains the leading risk factor, many lung cancers arise in people who would not qualify for screening under existing criteria, including never-smokers and individuals exposed to environmental pollutants.

The research team sought to develop a biologically informed method of identifying risk by focusing on inflammation, which has emerged as a critical driver of tumor development.

Previous work from the group demonstrated that air pollution can promote lung cancer by triggering inflammatory responses that awaken dormant cells carrying cancer-causing mutations. The new study aimed to determine whether this inflammatory state could be detected in the blood before cancer becomes clinically apparent.

Machine learning identifies a 14-protein signature

Using plasma protein measurements from more than 48,000 participants in the UK Biobank, researchers applied machine learning approaches to identify blood proteins associated with future lung cancer diagnoses.

The algorithm incorporated conventional risk factors such as age, smoking status, prior lung disease, and plasma protein profiles. Analysis revealed a panel of 14 circulating proteins that consistently predicted lung cancer risk within five years of diagnosis.

The signature was validated across eight independent international datasets and remained predictive across diverse populations, including a cohort composed entirely of non-smokers.

Individuals who later developed lung cancer consistently exhibited elevated levels of the signature years before their diagnosis.

“This is a proof of concept that, one day, we could use this signature to offer preventive treatment to people at risk of lung cancer,” said Tej Pandya, clinical PhD student at UCL and visiting scientist at The Francis Crick Institute.

Detecting an inflammatory state before cancer emerges

One of the study’s most significant findings is that the signature appears to reflect a pre-cancerous inflammatory environment rather than the presence of an undetected tumor.

The researchers found evidence that the protein profile originates from changes within the lung microenvironment before malignant transformation occurs.

Further analyses showed that the same signature was elevated in individuals who later developed chronic obstructive pulmonary disease (COPD) or idiopathic pulmonary fibrosis, suggesting it may identify a broader inflammatory state that predisposes individuals to multiple lung diseases.

Studies in mouse models provided additional support for this hypothesis. Exposure to air pollution increased both the protein signature and the abundance of a cellular state known as KAC cells—adaptive cells that emerge during tissue injury but can become malignant when cancer-driving mutations are present.

Mutant cells arising from several distinct lung cell populations converged on this same KAC state during the earliest stages of cancer development.

Linking air pollution, inflammation, and cancer

The findings build on earlier research implicating the inflammatory cytokine interleukin-1 beta (IL-1β) as a critical mediator of pollution-driven lung cancer.

The investigators demonstrated that air pollution exposure increased IL-1β signaling, elevated components of the 14-protein signature, and expanded KAC cell populations.

Blocking IL-1β in mice reduced KAC cell numbers and slowed early tumor formation, providing experimental evidence that inflammatory signaling contributes directly to cancer initiation.

These observations suggest that the blood signature may serve not only as a risk marker but also as a biological indicator of an underlying process that can be therapeutically targeted.

Revisiting a major clinical trial

To determine whether the signature could identify patients most likely to benefit from preventive intervention, the researchers revisited data from the landmark CANTOS trial.

The trial originally evaluated the IL-1β inhibitor canakinumab for cardiovascular disease prevention and unexpectedly reported reduced lung cancer incidence as an exploratory outcome. However, the overall cancer-prevention benefit appeared too modest to justify widespread use of the drug for this purpose.

The new analysis tells a different story.

Researchers examined data from 4,651 CANTOS participants and found that individuals with elevated levels of the 14-protein signature experienced the greatest benefit from canakinumab treatment. In this high-risk subgroup, lung cancer incidence was nearly cut in half.

By restricting treatment to those identified by the biomarker signature, the number needed to treat to prevent one lung cancer case fell to 55, a figure comparable to widely accepted cardiovascular prevention strategies such as statin therapy.

Toward precision cancer prevention

The work represents a shift in how researchers think about cancer prevention.

Rather than treating large populations indiscriminately, the study suggests that molecular biomarkers could identify individuals in a reversible pre-disease state and guide targeted interventions before cancer develops.

“Drugs like statins have transformed the prevention of cardiovascular disease, used to treat individuals with a high low-density lipoprotein (LDL),” said Charlie Swanton, FRCP, PhD, clinical research director at The Francis Crick Institute and professor of cancer at UCL.

“But we don’t yet have an LDL-like marker of risk or a statin for lung cancer.”

Swanton added that identifying an inflammatory state before tumor formation provides a potential “window of opportunity” in which preventive treatment could be most effective.

Implications beyond lung cancer

The investigators note that the inflammatory signature may reflect a broader biological phenomenon associated with aging and chronic disease.

Because the signature was also associated with future COPD and pulmonary fibrosis, it may represent a shared pre-symptomatic inflammatory state that precedes multiple age-related lung disorders.

If validated in prospective studies, the approach could ultimately support routine blood-based risk assessment and targeted prevention strategies not only for lung cancer but potentially for other inflammation-driven diseases.

For now, the findings provide one of the strongest demonstrations yet that cancer risk can be detected years before diagnosis and that those biological signals may be actionable.

The challenge ahead will be determining whether identifying high-risk individuals and intervening early can translate into measurable reductions in lung cancer incidence, a question future prospective prevention trials will seek to answer.

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Microglial State Shift May Determine Whether Alzheimer’s Disease Pathology Leads to Dementia

Researchers from the VIB-KU Leuven Center for Neuroscience, the UK Dementia Research Institute, and Muna Therapeutics have discovered a biological transition that occurs in Alzheimer’s disease (AD) that may influence whether the accumulation of amyloid-β plaques and tau pathology progresses to dementia. Using human brain tissue from octogenarians with and without dementia as well as cognitively healthy centenarians, the team found that a shift in the behavior of microglia occurs at a critical point between amyloid-driven inflammation and tau-associated neurodegeneration. The research, published in Nature Medicine, point to these microglial transitions as a potential new target for treating the disease.

“This has been an exciting journey with many partners,” said co-senior author Bart De Strooper, MD, PhD, a professor at VIB-KU Leuven Center for Neuroscience, Belgium. “The study, entirely based on human donor material, provides insight into one type of resilience mechanism in the progression of AD to dementia.”

Alzheimer’s disease affects more than 55 million people worldwide, but prior research has not been able to fully explain why some people with AD remain cognitively healthy despite having significant amounts of amyloid plaques and tau tangles in their brains. Current models of AD progression have assumed a linear path from amyloid accumulation to tau pathology, neurodegeneration, and cognitive decline. However, observations of cognitively intact older adults with substantial pathology have indicated there may be other biological factors that influence dementia development.

“AD is not an inevitable outcome of pathology but a dynamic process shaped by how brain cells respond to amyloid-β (Aβ) and tau,” the researchers wrote, adding that “Clinical symptoms may thus arise only when these compensatory mechanisms fail, crossing inflection points that shift the brain from adaptation to degeneration.”

Previous studies using single-cell and spatial transcriptomics had shown that microglia, astrocytes, oligodendrocytes, and neurons undergo stage-specific changes in response to amyloid accumulation. Those findings, combined with observations that some centenarians maintain cognition despite extensive pathology, suggested that immune-cell responses might influence disease outcomes and were the underpinnings of the current research.

To further understand these mechanisms, the investigators examined 24 well-characterized octogenarian brains and 20 brains from cognitively intact centenarians enrolled in the Dutch 100-plus Study. Using spatial transcriptomics, single-nucleus RNA sequencing, and in situ hybridization to tissue from the superior frontal gyrus, the team was able to analyze gene activity at single-cell resolution while preserving the spatial relationships between cells and pathological features in the brain.

Their analysis identified six distinct tissue domains representing a continuum of Alzheimer’s disease progression. Within this “spatial pathological” continuum of AD the researchers found a “key inflection point marked by a shift from Aβ-associated inflammatory changes to tau-associated cellular programs.”

This transition coincided with a significant change in microglial behavior. Early in the disease process, microglia adopted inflammatory states associated with amyloid plaques. Later, they shifted into antigen-presenting states linked to emerging tau pathology. The researchers described these as early and late plaque-induced gene, or PIG, programs.

Data from the study indicated that resilience to disease progression involved different microglial responses in the different groups studied. Octogenarians who accumulated amyloid plaques but remained free of dementia mounted the early inflammatory microglial response but did not progress to the later antigen-presenting state. This compared with cognitively intact centenarians in which the later microglial program was activated, but this activation occurred without the corresponding buildup of tau pathology typically associated with neurodegeneration.

“Resilient individuals showed distinct pathological patterns: octogenarians without dementia lacked late PIGs, whereas centenarians showed late PIG activation that was uncoupled from tau accumulation,” the researchers wrote.

According to the investigators, these findings indicate that resilience to development of dementia in AD is not simply a matter of avoiding pathology, but may depend on how the brain regulates the cellular consequences of AD pathology.

The research also revealed clues about how microglia might be targeted therapeutically. The researchers suggest that preserving beneficial early microglial functions involved in amyloid clearance and synaptic maintenance while preventing chronic antigen-presenting activation associated with tau pathology could help slow disease progression. Potential targets include pathways involving TREM2, CSF1R, and molecules associated with microglial state transitions.

“These findings open new opportunities to target microglial states—especially pathways such as TREM2—and extend resilience rather than simply focusing on plaque removal,” said co-senior author Niels Plath, PhD, chief scientific officer of Muna Therapeutics. “We are excited to continue this journey and understand the causal role of microglial transitions leading to the identification of novel therapeutic approaches to delay or prevent disease progression.”

Continued research will look to determine the causal mechanisms that drive these microglial state transitions and identifying the genetic, immune, or aging-related factors that allow some individuals to remain resilient despite significant Alzheimer’s pathology.

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Universal Coronavirus Vaccine Could Provide Protection Against Future Strains

Results from the first human trial of a universal coronavirus vaccine show early promise for a new approach to vaccine design that could protect against a broad range of strains within major virus groups, including strains that have not emerged yet. These findings were published today in the Journal of Infection.  

“Viruses like influenza, coronaviruses, and the Ebola group are evolving continuously and by the time vaccines are rolled out, they may be poorly matched. The current “reactive” vaccine system struggles to keep pace,” said Saul Faust, PhD, professor of pediatric immunity and infection at the University of Southampton and director of the NIHR Southampton Clinical Research Facility, who acted as chief investigator of the clinical trial.

Currently, vaccines contain antigens from specific viral strains that have been detected and predicted to be circulating in humans seasonally. However, because viruses mutate rapidly, the protection these vaccines offer can be limited by the time the vaccines are manufactured and distributed. In contrast, the PanSarbeco vaccine evaluated in this trial is designed to train the immune system to recognize and fend off a broad range of Sarbeco coronaviruses, including the SARS-CoV2 virus responsible for the COVID-19 pandemic.  

“This new class of universal vaccines are future-proofed,” said Faust. “They not only protect against many variants simultaneously, but potentially against related viruses that haven’t yet emerged and spilt over to humans. If we can develop and clinically advance this new class of vaccines before a virus outbreak begins, millions of lives could be saved, lockdowns avoided, and the economy preserved.”

The technology behind this vaccine uses machine learning to design a super antigen that can provide lasting protection against a broad range of viruses within a group, such as the Ebola group or the Sarbeco coronavirus group, even as they continue to mutate and evolve. This approach originated at the University of Cambridge and is currently being developed by DIOSynVax (Digitally Immune Optimised Synthetic Vaccines), a spin-out company established in 2017. 

“We’ve converted vaccine development from being reactive to being future proof. Our vaccines will continue to provide protection against viruses even as they mutate into new strains,” said Jonathan L. Heeney, DVM, PhD, professor of comparative pathology at the University of Cambridge and chief scientific officer of DIOSynVax. “We’ve overcome the problem of traditional vaccines, which have limited protection. It means we can escape the constant cycle of chasing the virus variants circulating in humans and updating the vaccines to try to catch up, like a dog chasing its tail.”

The PanSarbeco vaccine was tested in 39 healthy volunteers between 18 and 50 years old at NIHR research facilities at Southampton and Addenbrookes Hospital. The super antigen is compatible with most vaccine delivery systems; in this study it was delivered as a DNA vaccine using a needle-free delivery system in two doses administered 28 days apart. All four doses tested were well tolerated by the participants, with no significant safety concerns reported. 

While participants developed immune responses to epitopes of sarbecovirus antigens conserved across strains, preliminary measurements of immunogenicity were modest in some participants potentially due to previous immunization with COVID-19 vaccines. Going forward, a larger Phase II trial will assess the vaccine’s ability to induce a strong, broadly protective immune response. 

“The remarkable success of this AI-designed ‘super-antigen’ trial marks a pivotal leap forward in our ability to deliver broad, lasting viral protection,” said Marian Knight, MBChB, DPhil, professor of maternal and child population health at the University of Oxford and scientific director for NIHR Infrastructure.

 

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Awakening from the Trance

This blog was originally posted by the TLC Foundation for BFRBs

Trichotillomania touches on all levels of human experience, from the neurological to the spiritual. It represents the interactions of brain chemistry, but also habituated physiological responses, sensory processing, behavior patterns, characteristic emotional states, perceptual styles and beliefs, and the sense of interconnectedness with others and the experience of faith. It is more than just a behavior, although it is most apparent when it manifests itself in that way.

Trichotillomania can be treated at all of these levels through different treatment approaches: medication, relaxation and response prevention, behavior modification, hypnotherapy, psychotherapy, cognitive therapy and visualization, group therapy and spiritual practices. The most effective approach will depend on the specific needs and circumstances of each individual at specific times, as well as on the compatibility of the personalities of the treatment provider and patient/participant.

In this article I will present my own view of treatment with a particular focus on how to understand and address the aspect of trance.

“Trance” is not a clinical term, but it is one which most pullers seem to recognize immediately as a significant part of the hair pulling experience: particularly when reading or watching TV. However, I believe that any time one is pulling, one has entered a trance state and that trance states occur with great frequency even at other times. To look at how to make use of this concept I will first describe what I think treatment needs to address.

Trichotillomania as a symptom: My approach is to look at what the behavior of pulling means to a particular person, and what it means about them. I view pulling as a symptom which indicates something about what is going on in that person’s life and can be best understood if we look at the context in which it occurs – both over time (how did it evolve), and ecologically (how does it fit into the network of the person’s relationships, commitments, self-perceptions, experiences of their own body and emotional states, etc.).

Symptoms are an indication of the existence of some other process. Just as a fever may reflect a viral infection, a repetitive behavior reflects an underlying mental activity. The symptom develops in response to the activity and one of its functions is to achieve some control over the consequences of that mental activity. I believe that trichotillomania indicates an attempted solution to a psychological challenge (or opportunity) one is facing in one’s life. However, it is an ineffective solution for two reasons. Firstly, it doesn’t alter the situation which has become challenging, and so the underlying causes remain unchanged. Secondly, by drawing attention onto itself it obscures those underlying causes. It distracts attention from them.

But the behavior, none the less, does have some purpose and utility. It relieves the anxiety of becoming too aware that there are challenges and opportunities which one feels unprepared to confront.

The role of emotions:

The mechanism which could be drawing one’s attention to these challenges and opportunities is the experience of emotional reaction. Emotions serve to amplify our perceptions of situations by making the good seem better and the bad seem worse. In that way, they lead us to focus on what is important to us so that we will take action. Being able to notice and interpret our emotions is something we learn as we grow up. Emotions represent a kind of language for helping us make meaningful choices as we engage with life.

But if these emotions were felt to be too overwhelming – if what they indicated felt too bad to be tolerated because we did not learn how to resolve the situations they drew attention to – then we eliminated them from our emotional vocabulary and we restricted our awareness of them. Now, when those situations reoccur, rather than notice our feelings of hopelessness and helplessness, we may turn to other mechanisms, more basic ones rooted in physical sensations, to occupy ourselves and restore some sense of order to the world.

So, in this model, the behavior of hair pulling is not an indicator of psychological inadequacy, but rather a lack of awareness. It reflects a split between awareness/thoughts and sensations/feelings. It is the result of an unknown mental process, something one has not been able to assimilate into one’s conscious thought, for which no words or language have been developed.

If this could be understood then I believe there would be less justification for feelings of shame connected with Trichotillomania, because Trichotillomania represents an underlying process outside of personal awareness, and thus is not something voluntarily chosen. (It would also answer the following disturbing statement frequently made to hair pullers: “You could stop if you really wanted to.”)

I have so far described how emotional activity and unconscious thoughts affect us in ways which we do not recognize. Despite this lack of recognition, we still need to adjust to them and regulate or organize ourselves. A good example of this is the way in which a fussy baby, if not picked up or fed when it wants to be, learns to get its thumb into its mouth and suck on it. It is finding a way to organize its reactions to its world by retreating into an attitude of self-sufficiency. In this way it solves the problems of the conflict it experiences between the emotions it feels and the lack of a way to take effective action about them in the outside world. It restores order by returning to a sensation-based activity which it has control over. It has learned to retreat into a trance.

The similarities between this example and the experience of hair pulling are striking. So how is Trichotillomania like a trance, exactly?

Trance:

The (Oxford) dictionary defines “trance” in these ways: a suspension of consciousness; a state of mental abstraction from external things; absorption, exaltation, rapture, ecstasy. Going into a trance is turning away from the world, suspending engagement with it, and entering a twilight zone of self-enchantment. The experience is one of being in between states: neither in one’s own mind, nor aware of one’s body. One has turned away, both from the rest of the world and from the rest of oneself.

It is a state in which one doesn’t think about what one feels, and doesn’t act on what one feels. One has turned away from the parts of the self which are concerned with action and purposefulness. In the trance state, a part of the personality takes over which doesn’t care about anything (except the act of pulling) and ignores the existence of time or consequences to one’s actions. It is the opposite of the perfectionist attitude so common to many hair pullers. Becoming entranced in the act of reading, for example, one detaches from the here and now, and allows this part of the personality to “come out”: while the cat’s away, the mouse plays. It is a secure, dependable, magical place in which one can avoid dealing with the stimulation of one’s spontaneous emotional responses to life.

If we look again at the role of emotions as amplifiers of perceptions, we see that what is happening in this state is that one is neither thinking about, nor acting on, what the emotions could be indicating. And as they indicate what is important so that action can be taken, the trance state eliminates the possibility of taking the action required.

How does this detaching process become chronic?

I believe it is the result of repeated experiences of failing to take effective action on what one’s emotions tell one is important. This failure can have many causes, but the result is that these important situations become perceived as challenging and threatening because they are felt as over stimulating. To protect oneself from discomfort, one disassociates from the situation. The part of oneself which perceives or feels what is going on is split off from consciousness. What remains conscious is the part which doesn’t feel and which preserves a sense of order and calm. Gradually, a gap develops between this external presentation of the self – as coherent, caring, positive – and an inner state of feeling confused, frustrated, and overwhelmed.

A false self develops, a self which appears to be more in control than is actually felt, and which one tries to believe in. The fear of having this façade penetrated adds greatly to the level of stress felt by hair pullers. Because this false self cannot be dropped when one’s gut reactions tell one to, one becomes trapped in a vicious circle that leaves one over stimulated (including the times when one merely seems to be bored), detaching from one’s body, and trying to regain control. A strong need is felt to reconnect to the body and feel grounded.‍

Trichotillomania as a return to the body:

The route to feeling in one’s body again is through becoming hyperaware and hypersensitive to sensation. This is a more basic and elementary experience of oneself: one cannot think or feel what is happening, so one uses a physical behavior to establish a link between unconscious inner experience and being in the real, physical world. This provides a solution to the twilight state of feeling detached. The sensation-focused behavior provides a substitute sense of being connected, and its ritualistic aspect creates a sense of soothing order rather than chaos.

So, looked at in this way, the act of pulling a hair actually represents the second stage of entering into a trance. The trance is triggered by the habitual reaction of disassociating rather than facing a situation which one perceives as overwhelming. But while an attitude of order and calm is being adopted (a state of “mental abstraction”), the experience of being detached from the feelings in the body becomes disorienting and the urgent need is felt to focus on the sensation of touching, playing with, and pulling hair. This provides the experience of concreteness and connectedness which allows the trance to continue.

Awakening:

What is needed is a process for regaining consciousness and turning back to engaging with life. How does one wake up? How can one build a sort of observational platform from which to watch the process of entering into a trance; one which can be separate from the process itself? I would suggest that rather than start with the ultimate goal of avoiding trance states altogether (which may be unreachable), a more pragmatic approach would be to learn how to wake up once one starts.

When we drive long distances on freeways and our attention wanders, we sometimes find ourselves drifting over into the next lane. If there were raised lane markers on the road, they would then alert us by causing a noise and a vibration as the car drove over them. That is the kind of alarm system we are looking for. It doesn’t prevent our minds from wandering, but it brings us back to the here-and-now experience before we get into trouble.

Such a system does exist: it is the sensation of a hair being pulled out. Once one hair is pulled, the opportunity exists to break the trance. That hair can be a signal to come back to the here and now rather than getting into the trouble of starting a pulling binge. (The goal of stopping at one hair pulled would also very likely include the benefit of making it much easier to commit to a realistic process of bringing the behavior within tolerable limits.)

How can one learn to stop at just one? Setting such a goal becomes much more possible if one understands one’s reasons for avoiding the goal until now. I have discussed in this article how Trichotillomania is a process which provides an attempted solution to an underlying tension. There is an inevitable anxiety about relinquishing a familiar, dependable behavior. A part of oneself therefore resists changing it and depends on the benefits it brings. This part has no intention of allowing any changes to occur unless one is prepared for the emotional experiences that follow, and it protects one from them.

A way to understand this resistance to change would be to think of the patterns of our behavior as a balanced mobile hanging from the ceiling. All its parts are interconnected and form a stable pattern. If we remove one of the parts, all of the others start to swing wildly until they settle into a new, substantially different formation. The intermediate stage of unbalanced, indeterminate movement could be likened to the feeling of overstimulation from one’s emotions when the ritualistic trance is denied.

To prepare for this change, an expanded awareness of emotional experience and what it teaches is indispensable. The remainder of this article offers some suggestions for work that can be done alone to expand this ability. This task is made much easier and more effective, however, when it is done in the context of a healing dialogue: either in individual or group therapy, or in a support group. This option deserves serious consideration because the act of communicating to another person helps bring one’s inner experiences into focus. Additionally, when there is the trust that the other person is willing not only to listen but to actively attempt to grasp what the speaker means from the speaker’s own point of view, the feeling of validation and recognition received makes awareness of the emotional states more bearable.

Reading the signals:

Part of the personal preparation which can be done is to establish intent to learn from what is found when one tries to read the signals. This would require a willingness to recognize that there are good reasons for what one feels rather than prejudging emotions as wrong, inappropriate, or proof of all the “bad” things one has come to believe about oneself. It also requires a willingness to feel discomfort, hurt, and vulnerability so that there can be a return to wholeness and the sense of being fully alive.

1. The most direct step is simply to ask yourself questions such as: What am I feeling? What is on my mind? Is something bothering me? What do I want right now? Is there something I should be doing? Special attention should be paid to the first answer that comes to mind, even if it very quickly disappears or seems insignificant. You should have an open mind and be prepared to be surprised. Before asking yourself these questions, stop the activity you are doing, if possible. If answers do not emerge the following techniques can be tried.

2. Let your body speak. Allow yourself to become aware of where you feel tension or discomfort. Imagine that that part of you has a voice and can answer the questions in Step One. Try asking follow-up questions to learn more.

3. Try exaggerating the physical state that you are in. That is, whatever movement your body is making or would like to make, take it to an extreme as if you were a very melodramatic actor or dancer who had no inhibitions. Again, think about how your body is expressing answers to the questions in Step One.

4. Visualize yourself as a child of about five and ask the questions of her or him. The answers should seem to be in the language of a 5-year-old. It might help to hold an object such as a cushion or stuffed animal to you as you try to make contact with yourself in this way. It also might help to combine this with some exaggeration of body expression. Additional questions you might ask could be: What do you need from me? Is somebody upsetting you? (See Reference 1.)

5. Write a question to the child, then switch your pen to your other hand and write the answer with that hand. You should write very quickly and with no attempt to make the writing more legible. Then switch your pen back to your original hand for a further question. Continue the dialogue, and the switching of hands, until no further clarification is necessary. The purpose of this technique is to facilitate the spontaneous flow of ideas. (See Reference 2.)

6. Write out the questions as complete sentences to be completed and complete the same question five times as quickly as possible. The questions would be rewritten as follows: Right now, I want….; or: I am upset because…. Allow any response to come forward. Often, a few unrevealing responses will be followed by one unexpected and more valuable one. (See Reference 3.)

7. Hold the hair which has just been pulled out and ask yourself: What did this hair give itself up for? A significant reason for the failure to stop hair pulling is the frequent presence of trance states, which enable one to deny the consequences of the behavior. Additionally, the experience of trance encourages one to focus on physical sensations such as the feeling of a hair being pulled, so as to achieve a greater sense of being connected to reality.

I have described how one enters a trance when certain situations trigger a habituated expectation of becoming overwhelmed. In self-defense one suspends consciousness of the challenge and retreats into a state of emotional detachment. The alternative to the trance, then, is to identify and assimilate the emotional cues about the situation so that appropriate action can be taken. The sensation of the first hair being pulled can serve as an alarm to awaken one from the trance and begin this process of self-evaluation and a return to an alert engagement with life.

Reference 1: Margaret Paul. Inner Bonding. San Francisco: Harper Collins, 1990.Reference 2: Lucia Cappachione. The Power of Your Other Hand. North Hollywood, CA: Newcastle Publishing, 1988.Reference 3: Nathaniel Branden. How to Raise Your Self-Esteem. New York: Bantam, 1987.

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Brain-Targeted Drug Discovery Barriers Drive Deep Science Ventures and Medicines Discovery Catapult Deal

Deep Science Ventures (DSV) and Medicine Discovery Catapult (MDC) agreed to collaborate to address challenges in delivering medicines into the brain.

One of medicine’s greatest challenges is ensuring that treatments reach the precise area of the body where they are needed. While recent scientific breakthroughs have identified numerous targets for neurological conditions, the difficulty of effectively transporting these treatments across the blood-brain barrier and into the central nervous system (CNS) remains a primary challenge for global health.

According to the World Health Organization’s Global Status Report on Neurology, over 40% of the global population is living with CNS diseases, making them a leading global cause of ill health and disability.

Directly addressing critical gaps in healthcare means these innovations have the potential to improve patient outcomes while creating clinical and commercial opportunities for biotech and pharma companies. Developing new solutions could unlock access for rare neurological disorders and expand treatment to large or underserved patient populations, including those with diseases such as Alzheimer’s, Parkinson’s, and various brain cancers.

The first phase of the partnership will see an in-depth review of the current medicines landscape conducted to identify opportunities for innovation. This information will then be used to identify systemic gaps in brain-entry technologies. The long-term ambition is for novel approaches that meet the investment criteria of the partners to be spun out into new ventures focused on high-impact solutions and to provide them with pre-seed funding.

Alzheimers research
Credit: Minerva Studio/Getty Images

A core part of DSV’s approach involves building future founding teams to form new companies that will address challenges across multiple sectors. Future founders will work on opportunities that have been pre-scoped by DSV, de-risking the standard founder proposition.

By combining DSV’s venture-building model with MDC’s drug discovery expertise and infrastructure, the partnership will aim to develop new approaches to ensure life-changing medicines reach the brain, according to Adam Tomassi-Russell, senior director, DSV.

“The blood-brain barrier remains one of the most complex issues in modern medicine and with over 40% of the world’s population facing neurological conditions, it’s imperative that we find an optimal solution to this problem,” said Tomassi-Russell. “By pooling our venture-creation expertise with MDC’s discovery capabilities, we can offer the right founders a frictionless environment in which to tackle the CNS delivery gap. If we can solve the ‘how’ of brain entry more effectively, we can unlock a new frontier of CNS therapeutics and address the huge unmet need in these diseases.”

“At MDC, we are committed to transforming bold ideas into better treatments,” added Nicola Heron, chief strategy officer, MDC. “This collaboration presents an opportunity to discover new technologies that could have a significant impact on patients and society. Through this partnership, we will strengthen the ecosystem for CNS innovation in the U.K. and beyond, enabling more medicines to reach patients faster.”

 

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Are AI chatbots making us lose control of our brains?

This week I’ve been at SXSW London. There’s been music, film, and a lot—and I mean a lot—of talk about AI. I also had the opportunity to sit down with Gloria Mark, a psychologist at the University of California, Irvine, who has spent the last 30 years studying how people interact with digital technologies.

Early in her career, the biggest concerns were the potential impacts of internet and email use on our brains. We may laugh those concerns off today, but it’s true that as the technologies became more ubiquitous and ingrained in our daily lives, our attention spans began to shrink.

Mark is worried that things are only getting worse. The title of our session was “Have we lost control of our brains?” Unfortunately, Mark told me, the answer is yes.

Around two decades ago, Mark started wondering about how our use of devices might affect our attention spans. She set up what she calls “living laboratories,” using sensors and trackers to monitor adult volunteers’ attention, mood, and behavior when they were using devices.

In 2003, she found that the average user had an attention span of around two and a half minutes. That’s how long people could spend focused on one thing before moving on to something else. “That surprised me at the time,” she told me during our session on Wednesday. “I thought: Wow, this is really short.”

But when she repeated the experiment in 2012, she found that attention spans had shrunk—all the way down to around 75 seconds on average, she said. In research she conducted between 2014 and 2020, attention spans shrank further still—to a mere 47 seconds, on average. Yikes.

And it’s not good for us. Mark told me that she’s found switching our attention so frequently is stressful. “We would have people wear heart rate monitors, and … we would see direct correlation between switching attention fast and stress going up,” she told me.

All this distraction makes it harder for us to get stuff done, too. “It just takes longer to do any single task if you’re switching your attention,” she told me. “It’s not great for performance. It’s not great for our emotional well-being.”

And that’s for adults. What about the effects of digital technologies on children? A few months ago, Meta (which owns Facebook and Instagram) and Google’s YouTube were ordered to pay millions of dollars in damages to a 20-year-old woman who had accused the companies of creating products that led her to develop a childhood addiction.

Just a couple of weeks ago, Meta settled another lawsuit, this one brought by a rural school district in Kentucky. The district had also accused the company of designing addictive products that were harmful to students and had sought more than $60 million to cover the costs of their mental-health needs. Around 1,200 other school districts are taking similar legal action against social media companies.

But social media isn’t all bad, all the time. It can provide opportunities for some people, including those from marginalized groups, to form connections that might otherwise be difficult. A 2024 survey of LGBTQ+ teenagers found that while some described social media as a place of rejection and fear, others described it as a place where they felt a sense of belonging, where they could develop friendships and cultivate their identity.

In truth, we can’t definitively say what effects using social media is having on children across the board, says Mark. “There have been lots and lots of studies, and the evidence is to date inconclusive,” she told me. (Despite what you might read in best-selling books on the subject.)

Mark is hopeful that large, long-term studies might finally start shedding a bit more light on this question. An effort of this nature is underway in Australia, which enacted a social media ban for under-16s at the end of last year.

Given this uncertainty over a 20-year-old technology, I wondered if Mark had any thoughts on the potential impacts of AI—an obviously much newer offering that within the space of a couple of years appears to have become deeply integrated into our digital lives.

She told me she’s worried.

When we put in effort to do something—such as evaluating or summarizing content—we’re doing what’s known as “depth of processing,” she told me. “When you’re actively engaged with information, you’re processing it on a very deep level,” she said. “Then you’re more likely to learn it, to understand it, [and] to retain it.”

That’s not happening when most people use AI bots like ChatGPT, Claude, and Gemini. When we ask these tools to write, summarize, or evaluate for us, we’re no longer doing that depth of processing. “You’re deferring your cognitive work to AI,” she said. “And it’s not good for us.”

The risk is that our cognitive abilities will weaken over time. “If you’re not constantly exercising your muscles, they can atrophy,” Mark said. “And that’s exactly what can happen with our minds.” People with weaker critical thinking skills are more likely to fall prey to misinformation, she added.

Interactions with AI-powered “synthetic companions” can be just as harmful. Relationships between human beings take work—time, effort, and understanding. None of that is needed if you’re forming a relationship with a sycophantic bot. The “muscle” we risk atrophying here is emotional intelligence, which surveys suggest is already on the decline, said Mark.

She’s not painting a particularly rosy picture.

“If we continue on this trajectory, attention spans are diminished, loneliness is rising, boredom is rising, emotional intelligence decreasing, and actually our sense of purpose, according to studies, is also decreasing,” she said.

Luckily, she thinks we can course-correct by changing our relationship with these technologies. The key factor is effort.

The more effort we put into something, the deeper the satisfaction we stand to gain, Mark told me. That means making an effort to read a book rather than skimming its summary, and to meet with friends in person when you can. Try not to use GPS in places where you can probably manage without it.

“I love technology; we can’t give it up,” she told me. “[But] we have to learn how to create new life routines.”

This article first appeared in The Checkup, MIT Technology Review’s weekly biotech newsletter. To receive it in your inbox every Thursday, and read articles like this first, sign up here.

Novel Intracellular Pathway Identified That Protects Against Viral and Bacterial Infection

A common concept of the immune system is that of white blood cells putting up a fight against invading pathogens in the bloodstream. Researchers have now detailed a separate but equally important route by which our bodies fight infection—directly inside already infected cells. The team, co-led by Leo James, PhD, and Tyler Rhinesmith, PhD, at MRC Laboratory of Molecular Biology, defined a previously undescribed method of fighting pathogen invaders—and which they called  “antibody-directed xenophagy” (ADX)—where cells can digest bacteria and viruses, including Salmonella and adenoviruses, that cross the cell membrane. The scientists found that regulation of ADX is dependent on the intracellular protein, TRIM21, which James’s lab had previously shown protects from viral infection by binding to antibody-coated viruses in the cell cytosol, triggering virus degradation.

“People have talked about viral xenophagy before as a sort of concept, but if you look in literature, there aren’t any good examples where people have shown this operating to potently block infection,” said James. “In our single study, we’ve gone from the discovery of something completely unknown [ADX], all the way through molecular mechanism, its function in cells into animals, and demonstrated physiological importance.”

The discovery of the ADX pathway may have potential future medical implications. While far more study is needed, the research points to the feasibility that antibody or small molecule therapeutics could be used to treat infections by marking pathogens in the blood so TRIM21 can recognize and jumpstart ADX once they enter cells.

James, Rhinesmith, and colleagues reported on their findings in Molecular Cell, in a paper titled “TRIM21 induces selective autophagy of viruses and bacteria,” stating, “We propose that TRIM21 evolved through competition with pathogens to induce autophagy of diverse and complex substrates, potentially explaining its versatility for targeted protein degradation.”

Typically, the body will respond to an infection by creating antibodies that latch onto the invaders in the blood to alert immune cells, such as white blood cells, to destroy them. Sometimes, those antibody-bound pathogens evade the immune cells and infect healthy cells. This is where antibody-directed xenophagy becomes involved.

Using CRISPR-Cas9 and quantitative imaging, the team determined that once an antibody-labeled pathogen enters a cell, ADX begins with the specialized protein TRIM21, which flags the pathogen with a ubiquitin marker that signals to the cell that it has been invaded.

TRIM21 is an intracellular E3 ubiquitin ligase protein that binds to antibodies and catalyzes ubiquitination. Prior work by James’s group had found that TRIM protects against viral infection by binding to antibody-coated viruses in the cell, triggering ubiquitination and viral degradation.

“Recently, we and others have shown that the degradative adaptability of TRIM21 extends to a wide range of additional substrates beyond viral capsid proteins,” the team further pointed out. “TRIM21 is an exceptionally versatile ubiquitin ligase that can be directed by antibodies to target oligomeric protein scaffolds, viral capsids, and proteopathic aggregates for intracellular degradation.”

However, the mechanism used by cells to degrade the tagged viruses wasn’t known. “… how such a large and complex substrate is quickly and efficiently degraded remains unclear.”

Rhinesmith, a post-doc in James’s group, conducted a genome-wide CRISPR-Cas9 knockout screen, individually removing every gene across the human genome and testing how its deletion impacted TRIM21-triggered degradation of viruses. The results were striking, revealing a previously undescribed process by which TRIM21 is able to trigger autophagy of cell-invading viruses.

Autophagy is a conserved cellular process through which damaged or toxic cellular components are delivered to specialist acidic organelles to be degraded and recycled. While this process plays a key role in maintaining cellular health, its ability to protect against invading viral pathogens hasn’t been well studied.

Staff scientist Anna Albecka developed a high-fidelity confocal microscopy platform that allowed the team to visualize previously unidentified events in the TRIM21 restriction mechanism. The team observed binding of TRIM21 to antibody-coated viruses inside cells, in real time. The microscopy results showed that after TRIM21 ubiquitinates the invading virus complex, ubiquitin stimulates the assembly of autophagy components around viruses, including LC3, a marker for membranous compartments called autophagosomes.

Working with Claudia Puri and David C. Rubinsztein at the U.K. Dementia Research Institute, Cambridge, the team used super-resolution microscopy to visualize the assembly of these autophagosome membranes around individual viral particles coated in antibodies and TRIM21. Together, these observations revealed the stepwise process by which incoming virions are incarcerated inside sealed, LC3-positive autophagosomes.

Albecka was further able to show that these virus-containing autophagosomes are ultimately delivered to acidic lysosomes, resulting in the degradation of each virus into harmless peptides and nucleotides. Significantly, the study suggests that antiviral autophagy is a highly effective strategy deployed by cells to protect themselves from infection, and provides new tools for investigating this process.

Inspired by the ability of TRIM21 to activate by clustering around clients of very different architectures, the team next sought to understand whether it could also intercept a completely different type of pathogen: bacteria. The team used antibodies and a novel live cell microscopy method to track bacterial growth inside mouse cells. They observed the same ADX pathway that intercepts viral infection also potently restricts the growth of intracellular Salmonella. This discovery is significant because it explains how TRIM21 is able to intercept and trigger the degradation of invading pathogens of many complex structures and diverse lineages. “Importantly, our data explain how TRIM21 can degrade large and highly complex substrates,” the authors stated. “The need to intercept and destroy phylogenetically and structurally diverse pathogens may have driven the evolution of TRIM21’s very broad substrate versatility.”

By leveraging the intrinsic flexibility of the autophagy pathway, ADX can adapt to and degrade a variety of large and difficult targets. The findings indicate that the cell does not require a bespoke defense strategy for every individual pathogen. Instead, it employs a universal strategy, reliant on TRIM21, to redirect the cell’s existing autophagy machinery to any harmful material tagged with antibodies. This adaptability makes ADX clinically important for human immunity and, excitingly, a potential target for therapeutic enhancement.

“TRIM21 is unique because it uses the antibodies attached to the invading virus or bacteria to alert the cell,” said James. Rhinesmith added, “We show in the paper that on top of non-enveloped viruses, it’s also able to target bacteria along the same pathway. It seems that you trigger ubiquitination of whatever pathogen has antibodies around it through TRIM21, and this is the key step that leads to autophagy of the bacteria or the virus.”

This ability for cells to fight back from the inside doesn’t appear limited to specific cells within our body. The research team tested for the presence and action of TRIM21 against adenovirus in a range of human cell lines, as well as living mouse models in the case of Salmonella. These experiments indicated that ADX-mediated immunity is likely ubiquitous throughout the human body. “TRIM21 is expressed from what we call an ‘interferon-stimulated gene,’ which means that it is upregulated during infection, so your body makes it all the time, everywhere,” said James. “And the reason why you make it everywhere is so that you can potentially protect any cell or tissue.”

Though ADX may sound like a backup for our immune system for when pathogens evade our first lines of defense, the authors noted that this could be an equally important primary mode of protective immunity. “Our data shows that without TRIM21, a significant component of protective immunity in vivo against viruses is lost. In practice, immunity works because we’ve got different mechanisms operating together,” James said.

TRIM21 is the first intracellular protein discovered to stimulate ADX immunity, but there may be others that have equally broad or specific pathogen targets. Part of the research team’s next steps is determining the existence of other ADX-stimulating proteins and what limitations there may be to TRIM21’s function.

The post Novel Intracellular Pathway Identified That Protects Against Viral and Bacterial Infection appeared first on GEN – Genetic Engineering and Biotechnology News.

The Download: AI-generated lawsuits and virtual power plants for data centers

This is today’s edition of The Download, our weekday newsletter that provides a daily dose of what’s going on in the world of technology.

How courts are coping with a flood of AI-generated lawsuits

Most days in her chambers, Judge Maritza Braswell, a federal magistrate judge in Colorado, sifts through stacks of documents written by people without a lawyer. The number of these filings has more than doubled compared to before 2023. She puts that jump down to AI. 

But while AI appears to be expanding access to justice, it doesn’t seem to be improving people’s chances of winning. Judges are starting to question what rights and duties chatbots should have as they stand in for lawyers. Lawmakers, meanwhile, are grappling with who should pay the price when chatbots produce bad legal advice.

Read the full story on how AI is reshaping access to the law.

—Michelle Kim

How virtual power plants could provide energy for data centers

Would you take a payment to ramp down your electricity use? Would it change anything if you were doing so to help power a local data center? A new project backed by Google will put those questions to the test.

The company has signed a deal to fund a virtual power plant in the largest power grid in the US. The system will group together devices like electric vehicles and smart thermostats, paying customers to adjust their usage when the grid is stretched.

The project could free up capacity for Google’s data centers—but there’s a catch: people might not play along. Find out what the future holds for these virtual power plants.

—Casey Crownhart

This story is from The Spark, our weekly newsletter giving you the inside track on all things climate. Sign up to receive it in your inbox every Wednesday.

The must-reads

I’ve combed the internet to find you today’s most fun/important/scary/fascinating stories about technology.

1 The EU has proposed new legislation to end its Big Tech dependence
The laws aim to boost domestic ​cloud, AI and semiconductors. (CNBC)
+ US firms would be blocked from critical public tenders. (Reuters $)
+ It also wants to make sure non-EU actors cannot disrupt tech services with a “kill switch.” (The Guardian)
+ But the proposal needs to be negotiated with EU member states. (Politico $)

2 Intelligence agencies warn Chinese spies are recruiting on LinkedIn
The Five Eyes alliance said Beijing is using job platforms for espionage. (BBC)
+ The spies are allegedly recruiting government and military staff. (Politico $)
+ The Chinese embassy in the UK condemned the accusations. (Bloomberg $)
+ Meet the man hunting the spies in your smartphone. (MIT Technology Review)

3 AI CEOs have called for a law protecting against biological weapons
They warn that synthetic DNA could be used for bioweapons. (Wired $)
+ Sam Altman, Dario Amodei, and Demis Hassabis joined the call. (WSJ $)
+ No one’s sure if synthetic mirror life will kill us all. (MIT Technology Review)

4 Firms are using Reddit to manipulate ChatGPT and Google AI search
They’re spamming subreddits to get posts scraped by chatbots. (404 Media)
+ What we’ve been getting wrong about AI’s truth crisis. (MIT Technology Review)

5 Meta keeps delaying the launch of its new AI model
The new Muse Spark ‌AI model API still has no release date. (WSJ $)
+ Which is hampering Meta’s plans to monetize its AI investments. (Reuters $)

6 For the first time, a US city has voted to permanently ban data centers
Monterey Park, California, voted in favor of the move. (LA Times)
+ Should we be moving data centers to space? (MIT Technology Review)

7 China is betting on household chore training to advance robotics
Data harvested in homes and factories provides a scaling edge. (Rest of World)
+ Gig workers are training humanoids at home. (MIT Technology Review)

8 Sam Altman will urge US lawmakers not to require AI model approvals
He’s advocating against proposals for new AI rules. (Reuters $)
+ His move comes after President Trump signed a new AI order. (Wired $)

9 Quantinuum raised $1.68 billion in an IPO as quantum computing rises 
Investors flocked to one of the fast-growing sector’s leaders. (Reuters $)

10 Someone finally wants to hire philosophers: Silicon Valley
Big tech hopes they will help build better machines. (The Atlantic $)

Quote of the day

“Historically, these companies have been very willing to play Russian roulette—and they’re playing another round.”

—Connor Leahy, an AI researcher, former hacker and US director of ControlAI, tells the Financial Times why he’s concerned about Anthropic’s relentless race to the top.

One More Thing

Tentacle of Octopus

HENRY HORENSTEIN/GETTY


What an octopus’s mind can teach us about AI’s ultimate mystery

Emily Bender, a linguist at the University of Washington, has developed a thought experiment she calls the octopus test. It involves an octopus learning to copy patterns in human writing and produce squiggles in response. But does the animal actually understand the language or are we merely projecting meaning onto it?

Bender’s octopus is a stand-in for AI systems like ChatGPT. The intelligence we see in these machines is also projected on them by us. The same applies to consciousness: we may claim to see it, but it remains unclear whether it is really there.

Read the full story on the debate over machines with minds.

—Will Douglas Heaven

We can still have nice things

A place for comfort, fun, and distraction to brighten up your day. (Got any ideas? Drop me a line.)

+ Discover where iconic sound effects actually came from in this fabulous audio history.
+ Need a serotonin boost? Then tune into this live puppy cam from Denali National Park.
+ Linux lovers can try 570 extinct operating systems at a new virtual museum.
+ Beethoven’s “Moonlight Sonata” becomes something entirely different in this lightning-fast bass guitar performance.