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Critics say a fierce law-and-order approach could undermine public health goals and advances in addiction treatment.Three teenage girls were found slumped in a car in the parking lot of a rural Tennessee high school last month, hours before graduation ceremonies. Two were dead from fentanyl overdoses. The third, a 17-year-old, was rushed to the hospital in critical condition. Two days later, she was charged with the girls’ murders.Listen to This ArticleFor more audio journalism and storytelling,

Based on genetic blueprints, individual amino acids are assembled into long amino acid chains, the proteins, in the protein factories of our cells, the ribosomes. Each newly formed protein starts with the amino acid methionine. This amino acid is often split off again during protein synthesis, as soon as the growing amino acid chain leaves the protein factory through the “ribosomal tunnel.” In these cases, the excision of methionine is essential to ensure the subsequent function of the corresponding proteins in the cell.
The enzymes causing this cleavage are already known. According to their function, they are called methionine aminopeptidases (METAPs). Up to now, it was unclear how METAPs come into contact with the protein factories and, just at the right place and moment, cause the excision of methionine from specific proteins. Biologists Elke Deuerling, Martin Gamerdinger and their team from the University of Konstanz (Germany), together with Nenad Ban and his colleagues from ETH Zurich (Switzerland), have now shed light on the subject. The results published in Science show: access of METAPs to protein factories is controlled by a “ribosomal gatekeeper” called NAC (short for “nascent polypeptide-associated complex”).
More extensive function than previously known
Only last year (2022), the team led by Deuerling and Gamerdinger was able to elucidate that NAC performs an important sorting function at the ribosomal tunnel: “We were able to show that NAC sits in front of the tunnel exit like a gatekeeper. There it controls the transport of proteins to the endoplasmic reticulum (ER) — the membrane network inside the cell — by specifically bringing together protein and transport molecule (SRP),” Deuerling summarizes the previous study results. In their new study, the researchers now show that the gatekeeper’s sorting function is more extensive and even more significant than previously known, and that NAC also ensures the correct methionine excision from nascent proteins.
In proteins transported to the ER, the first amino acid methionine is part of a transport signal. “Methionine excision in these proteins would destroy the signal and thus prevent its transport into the cell’s membrane network, which would inevitably lead to cell death,” Gamerdinger explains. How these transport signals are prevented from being destroyed by METAPs was a major scientific puzzle the scientists from Konstanz and Zurich have now solved: The gatekeeper NAC forms a complex with METAP1 and the ribosome at the exit of the ribosomal tunnel. Only within this complex can the enzyme cause the excision of methionine from newly formed proteins.
This changes as soon as a protein with a transport signal leaves the ribosomal tunnel. Interactions between the protein’s signal sequence and NAC then cause the gatekeeper to change its own position at the ribosomal tunnel. As a result, METAP1 loses its binding to NAC and thus its ability to cleave off methionine. With the changed position of the gatekeeper, a new binding interface becomes accessible for the transport molecule SRP. “This mechanism means that proteins lacking signal sequences can be specifically modified by methionine excision. Those, in contrast, that are transported to the endoplasmic reticulum, remain unaffected by METAP1,” Gamerdinger explains.
The gatekeeper as a mediation all-rounder?
The researchers hypothesize that NAC may have other similar mediating functions at the ribosomal tunnel, thus assuming the role of a general molecular control centre. “There is a large number of enzymes and transport molecules that, like METAP1 and SRP, interact with the nascent proteins already during protein synthesis. Future studies will therefore have to show whether NAC also plays a role in regulating other processes that are vital for the function of our cells,” says Deuerling.

Clinicians have a new standard for graft-versus-host disease (GVHD) prevention after allogeneic hematopoietic stem cell transplantation, according to results from a phase III study published June 22 in the New England Journal of Medicine. The new standard is more effective at preventing GVHD and came with less side effects, compared with the current gold standard.
“The new standard allows transplants to be less toxic,” says lead study author Javier Bolaños-Meade, M.D., professor of oncology at the Johns Hopkins Kimmel Cancer Center.
In an allogeneic bone marrow transplant, the healthy stem cells come from the bone marrow of a relative who is not an identical twin of the patient or from an unrelated donor who is genetically similar to the patient. But a bone marrow transplant can cause GVHD, a serious and life-threatening complication. For decades, researchers in the bone marrow transplant community have been interested in decreasing the rates of GVHD, which occurs when the donor’s immune system reacts against the recipient’s tissue. As opposed to an organ transplant where the patient’s immune system will attempt to reject only the transplanted organ, in GVHD the new or transplanted immune system can attack the entire patient and all organs.
“At Hopkins we have been studying better alternatives to decrease GVHD,” says Bolaños-Meade. “Since the late 1990s, early 2000s, we at Hopkins have been studying the role of a high-dose, post-transplantation, cyclophosphamide-based platform.”
The current gold standard to prevent GVHD after bone marrow transplants is a combination of two drugs: a calcineurin inhibitor, such as tacrolimus or cyclosporine, and methotrexate. In the current phase III study, researchers from multiple institutions tested this standard to prevent GVHD against an experimental regimen of three drugs: cyclophosphamide, tacrolimus, and mycophenolate mofetil. Patients were recruited and randomized to either arm. This was done during the COVID-19 pandemic, but despite that, the study completed accrual ahead of time: 431 patients were enrolled from 37 centers across the United States. Patients were HLA matched to donors if related, and if unrelated, they were to be matched but could have one antigen mismatch. It took two years to enroll all patients (6/19 to 6/21) and patients were followed for at least one year.
Patients achieved the primary endpoint if they were alive, without acute GVHD grade III-IV, without chronic GVHD needing immunosuppression, and without relapse or progression from their cancer. At one year, the probability of achieving the endpoint was 52.7% for those getting the cyclophosphamide platform compared with 34.9% for those getting methotrexate and tacrolimus.
“More than half patients in the cyclophosphamide platform were alive, free of grade III-IV acute GVHD and chronic GVHD needing immunosuppression, and without disease relapse or progression versus a third in the methotrexate and tacrolimus arm,” says Bolaños-Meade. “There were also a series of secondary endpoints showing less severe acute GVHD, and less chronic GVHD. Very importantly this was seen without an increase on relapses as historically — the better control of GVHD, the more cancer relapses. In this case we have better control of GVHD, but no more relapses.”
The researchers say that for the first time since the 1980s, we have a more effective drug therapy to prevent severe cases of GVHD, and therefore, we have a new standard of care. “This is important because methotrexate and tacrolimus is toxic enough. Now our transplants can be performed even in older individuals. In fact, the median age in the study was 66 years,” says Bolaños-Meade.
Support for this study was provided by grants #U10HL069294 and #U24HL138660 to the Blood and Marrow Transplant Clinical Trials Network from the National Heart, Lung, and Blood Institute and the National Cancer Institute.

The NewsSales of e-cigarettes rose by nearly 47 percent from January 2020, just before the pandemic hit the United States, to December 2022, according to an analysis released on Thursday by the Centers for Disease Control and Prevention.The increase over that period occurred while teenagers and young adults reported in surveys that they had recently tried e-cigarettes at much higher rates than older adults did.According to the C.D.C., about 4.5 percent of all adults said they used e-cigarettes. But the rates went up as the age dropped. About 14 percent of high school students and 11 percent of young adults reported using the devices within the last 30 days of the survey, the C.D.C. data showed.Sales were still growing through May of last year, but then dropped by 12 percent through December. Researchers attributed the decline to several possible factors, including state or local bans on flavored products; government enforcement; and the introduction of devices that offered thousands of “puffs” in a single device.Overall, four-week sales of e-cigarettes climbed to 25.9 million units late last year, from 15.5 million units in early 2020.A health warning accompanies the display of Vuse e-cigarettes.Michael M. Santiago/Getty ImagesWhy It Matters: Effects of vaping are still unknownThe Food and Drug Administration has embraced the use of e-cigarettes, regulating their sale on the market as an aid for adult smokers to make the transition to a less harmful product.But tobacco opponents and public health experts warn that the popular devices have lured teenagers and young people — who would be unlikely to smoke traditional cigarettes — into an addictive habit amid growing concerns about vaping nicotine.The C.D.C.’s analysis reinforces data indicating that fruit and candy flavors have surged in popularity. The vaping devices often contain high levels of nicotine and are sold in appealing colors and flavors, like strawberry ice cream and mango ice.The American Heart Association has called for more action to reduce youth vaping and issued a scientific statement last year saying that e-cigarettes appeared to lead to increased risk of heart and lung disease. The American Lung Association has also aired concerns, saying it was “very troubled by the evolving evidence about the impact of e-cigarettes on the lungs” and citing the known and unknown toxic effects of chemicals used in vapes.Background: Youth vaping was on the riseThe C.D.C. study does not include sales from vaping and tobacco shops or internet sales, so the findings are limited.Still, trends have shifted in the last few years. Vaping of e-cigarettes among minors has declined from a record high in 2019, when nearly 28 percent of high school students reported vaping within the last 30 days. At the time, products that were sleek and produced by Juul Labs were the most popular, and the company was largely blamed for the soaring rate of teenage vaping. Juul has since resolved myriad lawsuits brought by many states and individuals, resulting in settlements adding up to nearly $3 billion.The F.D.A. has rejected applications for millions of products to get on the market, approving only about two dozen tobacco-flavored vaping devices. Yet the agency has struggled with enforcement; flavored vapes have flooded gas stations, convenience stores and vape shops nationwide.The agency prevailed in court in recent weeks against the makers of Hyde vapes, which were a favorite among high school students in a recent youth tobacco survey. The latest report from the C.D.C. shows Elf Bar Vapes rising in popularity. The F.D.A. has issued an import alert for them to be seized at the border and on Thursday announced enforcement against nearly 200 retailers selling those vapes and Esco Bar products.What’s Next: Regulation and enforcementThe F.D.A. has said it will issue final decisions by the end of this year on the remaining applications for selling vaping products to address the top sellers by Vuse, Juul and others.Tobacco control advocates are pressuring the F.D.A. to step up its enforcement of unauthorized e-cigarettes and to also move forward with a proposed ban on menthol cigarettes.Many interested parties are also watching the effects of a statewide flavor ban unfolding in California — one similar to those in six other states and more than 300 jurisdictions. Since Dec. 21, when the ban took effect, vape product sales fell 35 percent through late March, according to data from the C.D.C. Foundation.

Researchers at Karolinska Institutet in Sweden have identified a group of nerve cells in the mouse brain that are involved in creating negative emotional states and chronic stress. The neurons, which have been mapped with a combination of advanced techniques, also have receptors for oestrogen, which could explain why women as a group are more sensitive to stress than men. The study is published in Nature Neuroscience.
Just which networks in the brain give rise to negative emotions (aversion) and chronic stress have long been unknown to science.
By using a combination of advanced techniques, such as Patch-seq, large-scale electrophysiology (Neuropixels) and optogenetics (see factbox), KI researchers Konstantinos Meletis and Marie Carlén and their team have been able to map out a specific neuronal pathway in the mouse brain leading from the hypothalamus to the habenula that controls aversion.
The researchers used optogenetics to activate the pathway when the mice entered a particular room, and found that the mice soon started to avoid the room even though there was nothing in it.
Opens the way for novel treatments for depression
“We discovered this connection between the hypothalamus and the habenula in a previous study but didn’t know what types of neurons the pathway was made up of,” says Konstantinos Meletis, professor at the Department of Neuroscience, Karolinska Institutet. “It’s incredibly exciting to now understand what type of neuron in the pathway controls aversion. If we can understand how negative signals in the brain are created, we can also find mechanisms behind affective diseases like depression, which will open the way for novel drug treatments.”
The study was led by three postdocs at the same department, Daniela Calvigioni, Janos Fuzik and Pierre Le Merre, and as Professor Meletis explains, is an example of how scientists can use advanced techniques to identify neuronal pathways and neurons that control emotions and behaviour.

Sensitive to estrogen levels
Another interesting discovery is that the neurons linked to aversion have a receptor for oestrogen, making them sensitive to oestrogen levels. When male and female mice were subjected to the same type of unpredictable mild aversive events, the female mouse developed a much more lasting stress response than the male.
“It has long been known that anxiety and depression are more common in women than in men, but there hasn’t been any biological mechanism to explain it,” says Marie Carlén, professor at the Department of Neuroscience. “We’ve now found a mechanism that can at least explain these sex differences in mice.”
The study was mainly financed by the Knut and Alice Wallenberg Foundation, the Swedish Research Council, the Swedish Brain Foundation and the David and Astrid Hagelén Foundation. The researchers report no potential conflicts of interest.
Factbox: Here are the techniques used
Patch-seq: Patch-seq combines measurements of the electrical properties of individual cells with measurements of gene expression (RNA sequencing) and makes it possible to map the different types of neurons in the brain.
Neuropixels: The Neuropixels probe is a new type of electrode for large-scale electrophysiological measurements that makes it possible record the activity of hundreds of individual neurons simultaneously.
Optogenetics: Optogenetics is used to control how and when selected neurons are active. The method involves introducing light-sensitive proteins (such as channel proteins from the membranes of single-cell organisms) into the neurons to be studied. Light can then be used to control individual cell types in the mouse brain to ascertain their function.

Small-cell lung cancer is a particularly aggressive type of tumor with a consistently high mortality rate. In recent years, the research of scientists at MedUni Vienna’s Department of Thoracic Surgery has significantly contributed to a better understanding and new therapeutic approaches in this malignant disease. Their comprehensive overview of new insights and advances in small-cell lung cancer has just been published in CA: A Cancer Journal for Clinicians, the highest-ranked international scientific journal.
The key findings of Balazs Döme’s team from the Department of Thoracic Surgery at MedUni Vienna primarily consist of new insights into the biology and heterogeneity of small-cell lung cancer (SCLC). In collaboration with colleagues from Sweden, the Czech Republic, Hungary, and the United States, the researchers previously demonstrated that SCLC can be categorized into different subgroups which are associated with varying clinical behaviors and potentially new therapeutic strategies. They also demonstrated that certain combinations of multiple drugs represent a particularly promising therapeutic approach in patients with characteristic molecular SCLC profiles.
Based on these profound research contributions, the team from the Translational Thoracic Oncology Research Laboratory at MedUni Vienna’s Department of Thoracic Surgery was recently invited to present a comprehensive overview of recent advances in small-cell lung cancer. The review from Balazs Döme and his team has now been published in the journal CA: A Cancer Journal for Clinicians, the flagship journal of the American Cancer Society with the highest impact factor (286) of any scientific journal worldwide.
“We are delighted that our research achievements have received such high recognition,” says Konrad Hötzenecker from the Department of Thoracic Surgery. “This provides an optimal base to further expand the clinical and translational lung cancer research activities of the Department of Thoracic Surgery at the Medical University of Vienna as one of the leading centers,” emphasizes the newly appointed Professor of Thoracic Surgery and Director of the Department Clemens Aigner.
Expediting the development of personalized therapies
Approximately 15 percent of lung cancer patients are affected by small-cell lung cancer. This particularly aggressive tumor, which usually occurs in smokers, grows rapidly, has an increased tendency to metastasize, and a high mortality rate. According to Balazs Döme, conventional therapies have reached their plateau of effectiveness in SCLC. “With our research work, we have already created the basis for the development of targeted, personalized therapeutic approaches, which we now want to advance further,” Döme states, announcing further research.

New research from the Institute of Psychiatry, Psychology & Neuroscience (IoPPN) at King’s College London has found that in a mouse model mimicking Alzheimer’s Disease (AD) pain signals are not processed in the same way as in healthy mice.
The research, published in Nature Communications, suggests that the perception of pain in people with Alzheimer’s Disease may be altered, and asks whether changes in management of pain in people with AD could improve their quality of life.
While chronic musculoskeletal pain is common in individuals with AD, it remains largely untreated as it can go unreported due to the cognitive deficits attached to the disease.
In this study, the researchers sought to explore whether there is also an alteration in the body’s response to pain by the nervous system in people with AD.
In healthy mice, pain signals are transmitted from the point of origin to the central nervous system to initiate an immune response. The protein Galectin-3 has been demonstrated to be responsible for pain signal transmission to the spinal cord. Upon reaching the spinal cord, it binds to another protein, TLR4, to initiate the immune response.
In this study, researchers used an AD mice model and gave them rheumatoid arthritis, a type of chronic inflammatory disease, through blood transfer. They observed an increase in allodynia, pain caused by a stimulus that doesn’t normally provoke pain, as a response to the inflammation. They also found and increased activation of a microglia — resident immune cells — in the spinal cord. They determined that these effects were regulated by TLR4.
Researchers found that the mice with AD lacked TLR4 in the immune cells of their central nervous system and were therefore unable to respond to pain in the typical way as the signals were not being perceived.
This resulted in the mice with AD developing less joint inflammation related pain, and a less powerful immune cell response to the pain signals received by the central nervous system.
Professor Marzia Malcangio, Professor of Neuropharmacology at King’s IoPPN and the study’s senior author said, “Nociceptive pain — pain which is the result of tissue damage — is the second most prevalent comorbidity in individuals with Alzheimer’s disease. Our study has shown that, in mice with Alzheimer’s, the body’s ability to process that pain is altered due to the lack of TLR4; a protein vital to the immune response process in the central nervous system.
“These are important findings, as untreated pain can contribute to the psychiatric symptoms of the disease. Increasing our understanding of this area could, with more research, lead to more effective treatments and ultimately improve people’s quality of life.”
George Sideris-Lampretsas, a PhD student at King’s IoPPN and the study’s first author said, “The results of this study have the potential to make an impact, not only by identifying Galectin-3/TLR4 as a potential therapeutic target for chronic pain, but most importantly by raising awareness around the underreported and untreated pain experienced by patients with AD.”

The genetic causes of very early menopause will have to be reconsidered after researchers found that nearly all women who carried variations thought to cause the condition in fact had their menopause at an older age.
Until now, variants in any one of more than 100 genes were thought to cause premature ovarian insufficiency (POI), which results in menopause before the age of 40 and affects around one per cent of women, making it a leading cause of infertility. Under current guidance, a variation in one of these genes is cause for clinicians to consider a genetic diagnosis of POI.
Now, in the largest study to date, published in Nature Medicine, a team led by the University of Exeter and the University of Cambridge analysed genetic data from more than 104,733 women in UK Biobank, of whom 2,231 reported experiencing menopause before the age of 40.
The study, funded by the Medical Research Council (MRC) and supported by the NIHR Exeter Biomedical Research Centre, found evidence that 98 percent of women carrying variations in the genes that were previously considered to be causes of premature menopause in fact had menopause over 40, therefore ruling out a diagnosis of POI in these women.
Anna Murray, Professor of Human Genetics at the University of Exeter Medical School is a senior author on the study. She said: “Our research means rethinking what causes very early menopause. The presence of specific genetic variants in multiple women who experience premature menopause has led to the assumption that they are causing the condition — but we have shown that these gene variations are also found in women with a normal age of menopause and therefore in many cases the link could just be coincidence. It now seems likely that premature menopause is caused by a combination of variants in many genes, as well as non-genetic factors. As genomic medicine evolves, we need to apply this standard of evidence to other conditions, so we can tailor diagnosis, treatment and support.”
Dr Julia Prague, Consultant Endocrinologist and Clinical Academic at the University of Exeter, and an author on the paper, said: “Having a very early menopause is often extremely distressing because it means losing fertility and treatment with hormone replacement is required to prevent negative health consequences. Clinicians need to understand the reasons why premature menopause occurs so that they do not miss the true underlying cause and can counsel patients appropriately. Misinterpreting genetic tests could have negative implications for women, such as suggesting that their relatives may also be at risk of very early menopause due to their genes, when in fact they may not be.”
Stasa Stankovic, of the University of Cambridge’s MRC Epidemiology Unit, and co-lead analyst of the study, said: “Each woman’s unique genetic combination shifts menopause timing, either earlier or later. Although genetic variation in the studied genes were not sufficient to cause very early menopause, we did identify genetic drivers that had a much more subtle impact on reproductive longevity. For example, women carrying genetic variation in TWNK and SOHLH2 genes experienced menopause up to three years earlier than the general population. Our future studies will continue using the power of human genomics to better understand the underlying biology of reproductive ageing in women and key genetic drivers of its extreme forms, including very early menopause. With this knowledge, we are also paving the path towards development of next-generation treatments for reproductive disorders.”

The herpes simplex virus-1 can sometimes cause a dangerous brain infection. Combining an anti-inflammatory and an antiviral could help in these cases, report scientists with the Rajewsky and Landthaler labs and the Organoid Platform at the Max Delbrück Center in “Nature Microbiology.”
About 3.7 billion people — 67% of us — carry the herpes simplex virus-1 in our nerves cells where it lies quiescent until triggered by stress or injury. When activated, its symptoms are usually mild, limited to cold sores or ulcers in our mouth.
Very rarely, the virus can travel up the neurons to the brain, where it can cause a life-threatening infection. This accounts for 5 to 15% of all cases of infectious encephalitis in children and adults. Doctors typically prescribe an anti-viral called acyclovir. But even so, the patients often suffer from long-lasting and debilitating memory loss, seizures and other cognitive disorders.
In such cases, doctors could trial an anti-viral in combination with a drug that curbs inflammation to see whether it offers a better prognosis, suggests a new “Nature Microbiology” study by scientists at the Max Delbrück Centre for Molecular Medicine in the Helmholtz Association in Berlin. The scientists made this discovery using a three-dimensional model of the brain grown from human stem cells. The use of such models, called organoids, is at the frontier of clinical medicine.
“These proto-brains contain hundreds of thousands of neurons that can communicate with each other in a synchronized manner. Important experiments can be conducted with them that were impossible a few years ago,” says Professor Nikolaus Rajewsky, Scientific Director of the Berlin Institute for Medical Systems Biology at the Max Delbrück Center (MDC-BIMSB) and senior author of the study.
Dr. Agnieszka Rybak-Wolf, who heads the Organoid Technology Platform at the Max Delbrück Center and is one of the first authors, created the organoids, which were white, 0.5 cm blobs. “Brain organoids look a bit like small clouds of tissue,” she says.

Closer to reality for herpes
Without organoids, analyzing HSV-1-induced encephalitis is challenging. The virus infects only people and getting these brain samples is impractical. Scientists defaulted to studying the disease in cultured nerve cells or in mice, which are not natural carriers of the virus.
“This model is now much closer to reality for the herpes virus than what has been used previously,” says Dr. Emanuel Wyler, a virus expert who studies the molecular mechanisms of HSV-1 infections at the Landthaler lab and one of the first authors.
The scientists infected the organoids with the HSV-1 virus and visualized the neuroepithelial and neuronal cells as the virus rampaged and the mini-brain disintegrated. “We had these beautiful microscopy images that are so clear and you can see what is actually going on,” Wyler says.
They next conducted a single cell analysis to identify all the molecular pathways active during infection. “We used an unbiased approach to find all the pathways and genes that matter,” says Dr. Ivano Legnini, a systems biologist previously at the Rajewsky lab, and one of the first authors. “We bring systems biology to the table.”
They noticed that a signaling pathway important in inflammation, called TNF-α, was highly active. When they treated the organoids with acyclovir, the standard of care for HSV-1 encephalitis, viral replication stopped — but the tissue damage continued. Further analysis showed the TNF-α pathway was still active despite treatment.

A defense that can become damaging
“The inflammation pathway is a key natural defense to the virus,” says Dr. Tancredi Massimo Pentimalli, a medical doctor now doing his PhD in systems medicine at the Rajewsky lab and one of the first authors. “But when we block viral replication with anti-viral drugs, the overzealous inflammatory response could instead become damaging.”
Rybak-Wolf treated the organoids with both an anti-viral and an anti-inflammatory drug, which would turn off the TNF-α pathway. This combined treatment prevented the damage of mini-brains. “There is a signaling pathway in the brain that becomes active during infection,” she says. “When we switched it off using these drugs, the organoid wasn’t damaged.”
The scientists hope doctors will trial acyclovir and an anti-inflammatory as a treatment for HSV-1 encephalitis. “I hope that clinical investigators will set up clinical trials evaluating the efficacy of new anti-viral and anti-inflammatory combination therapies in herpes encephalitis patients, ultimately translating our findings from the bench to the bed side,” Pentimalli says.

The brain and the digestive tract are in constant communication, relaying signals that help to control feeding and other behaviors. This extensive communication network also influences our mental state and has been implicated in many neurological disorders.
MIT engineers have now designed a new technology that can be used to probe those connections. Using fibers embedded with a variety of sensors, as well as light sources for optogenetic stimulation, the researchers have shown that they can control neural circuits connecting the gut and the brain, in mice.
In a new study, the researchers demonstrated that they could induce feelings of fullness or reward-seeking behavior in mice by manipulating cells of the intestine. In future work, they hope to explore some of the correlations that have been observed between digestive health and neurological conditions such as autism and Parkinson’s disease.
“The exciting thing here is that we now have technology that can drive gut function and behaviors such as feeding. More importantly, we have the ability to start accessing the crosstalk between the gut and the brain with the millisecond precision of optogenetics, and we can do it in behaving animals,” says Polina Anikeeva, the Matoula S. Salapatas Professor in Materials Science and Engineering, a professor of brain and cognitive sciences, associate director of MIT’s Research Laboratory of Electronics, and a member of MIT’s McGovern Institute for Brain Research.
Anikeeva is the senior author of the new study, which appears today in Nature Biotechnology. The paper’s lead authors are MIT graduate student Atharva Sahasrabudhe, Duke University postdoc Laura Rupprecht, MIT postdoc Sirma Orguc, and former MIT postdoc Tural Khudiyev.
The brain-body connection
Last year, the McGovern Institute launched the K. Lisa Yang Brain-Body Center to study the interplay between the brain and other organs of the body. Research at the center focuses on illuminating how these interactions help to shape behavior and overall health, with a goal of developing future therapies for a variety of diseases.

“There’s continuous, bidirectional crosstalk between the body and the brain,” Anikeeva says. “For a long time, we thought that the brain is a tyrant that sends output into the organs and controls everything. But now we know that there’s a lot of feedback back into the brain, and this feedback potentially controls some of the functions that we have previously attributed exclusively to the central neural control.”
Anikeeva, who directs the new center, was interested in probing the signals that pass between the brain and the nervous system of the gut, also called the enteric nervous system. Sensory cells in the gut influence hunger and satiety via both the neuronal communication and hormone release.
Untangling those hormonal and neural effects has been difficult because there hasn’t been a good way to rapidly measure the neuronal signals, which occur within milliseconds.
“To be able to perform gut optogenetics and then measure the effects on brain function and behavior, which requires millisecond precision, we needed a device that didn’t exist. So, we decided to make it,” says Sahasrabudhe, who led the development of the gut and brain probes.
The electronic interface that the researchers designed consists of flexible fibers that can carry out a variety of functions and can be inserted into the organs of interest. To create the fibers, Sahasrabudhe used a technique called thermal drawing, which allowed him to create polymer filaments, about as thin as a human hair, that can be embedded with electrodes and temperature sensors.

The filaments also carry microscale light-emitting devices that can be used to optogenetically stimulate cells, and microfluidic channels that can be used to deliver drugs.
The mechanical properties of the fibers can be tailored for use in different parts of the body. For the brain, the researchers created stiffer fibers that could be threaded deep into the brain. For digestive organs such as the intestine, they designed more delicate rubbery fibers that do not damage the lining of the organs but are still sturdy enough to withstand the harsh environment of the digestive tract.
“To study the interaction between the brain and the body, it is necessary to develop technologies that can interface with organs of interest as well as the brain at the same time, while recording physiological signals with high signal-to-noise ratio,” Sahasrabudhe says. “We also need to be able to selectively stimulate different cell types in both organs in mice so that we can test their behaviors and perform causal analyses of these circuits.”
The fibers are also designed so that they can be controlled wirelessly, using an external control circuit that can be temporarily affixed to the animal during an experiment. This wireless control circuit was developed by Orguc, a Schmidt Science Fellow, and Harrison Allen ’20, MEng ’22, who were co-advised between the Anikeeva lab and the lab of Anantha Chandrakasan, dean of MIT’s School of Engineering and the Vannevar Bush Professor of Electrical Engineering and Computer Science.
Driving behavior
Using this interface, the researchers performed a series of experiments to show that they could influence behavior through manipulation of the gut as well as the brain.
First, they used the fibers to deliver optogenetic stimulation to a part of the brain called the ventral tegmental area (VTA), which releases dopamine. They placed mice in a cage with three chambers, and when the mice entered one particular chamber, the researchers activated the dopamine neurons. The resulting dopamine burst made the mice more likely to return to that chamber in search of the dopamine reward.
Then, the researchers tried to see if they could also induce that reward-seeking behavior by influencing the gut. To do that, they used fibers in the gut to release sucrose, which also activated dopamine release in the brain and prompted the animals to seek out the chamber they were in when sucrose was delivered.
Next, working with colleagues from Duke University, the researchers found they could induce the same reward-seeking behavior by skipping the sucrose and optogenetically stimulating nerve endings in the gut that provide input to the vagus nerve, which controls digestion and other bodily functions.
“Again, we got this place preference behavior that people have previously seen with stimulation in the brain, but now we are not touching the brain. We are just stimulating the gut, and we are observing control of central function from the periphery,” Anikeeva says.
Sahasrabudhe worked closely with Rupprecht, a postdoc in Professor Diego Bohorquez’ group at Duke, to test the fibers’ ability to control feeding behaviors. They found that the devices could optogenetically stimulate cells that produce cholecystokinin, a hormone that promotes satiety. When this hormone release was activated, the animals’ appetites were suppressed, even though they had been fasting for several hours. The researchers also demonstrated a similar effect when they stimulated cells that produce a peptide called PYY, which normally curbs appetite after very rich foods are consumed.
The researchers now plan to use this interface to study neurological conditions that are believed to have a gut-brain connection. For instance, studies have shown that children with autism are far more likely than their peers to be diagnosed with GI dysfunction, while anxiety and irritable bowel syndrome share genetic risks.
“We can now begin asking, are those coincidences, or is there a connection between the gut and the brain? And maybe there is an opportunity for us to tap into those gut-brain circuits to begin managing some of those conditions by manipulating the peripheral circuits in a way that does not directly ‘touch’ the brain and is less invasive,” Anikeeva says.