Short-lived neural connections in the mouse brain help prime sensory circuits, forever affecting the mouse’s sense of touch. Cold Spring Harbor Laboratory neuroscientists have discovered that a receptor protein named mGluR1 helps regulate the timing of these temporary connections. Their findings may help reveal the origins of various neurodevelopmental disorders and new ways of treating them.
Not everything in the brain is meant to last. As our brains assemble, trillions of neural connections have to be built or torn down at the right time and place. Otherwise, the seeds of conditions like autism can take root. Cold Spring Harbor Laboratory Assistant Professor Gabrielle Pouchelon studies how the brain is wired early in life. In doing so, she hopes to find the origins of various brain dysfunctions and new ways to treat them.
In a new study, Pouchelon and her team zero in on a process known as pruning. This is when the brain removes unnecessary connections between neurons. The pruning of long-lasting connections is relatively well-known. Pouchelon’s team focuses on special early connections that get cut to make way for long-lasting circuits in the mature brain. Though temporary, these early connections may play a critical role in shaping developing brain circuits.
Pouchelon’s lab has now discovered that a receptor protein named mGluR1 helps regulate the timing of these temporary connections in the mouse brain. Her team found that without mGluR1, neural connections stick around too long in the brain region that controls and processes touch via the whiskers. When the sensory circuit fails to mature properly, the mice demonstrate atypical behaviors. For example, they don’t stand on their hind legs and sniff around the way other mice do.
Importantly, the team notes that this critical step in circuit development occurs during the first week after birth. “The way the receptor works seems to be different than what has been described in adulthood,” Pouchelon says. “In the context of neurodevelopmental disorders, that means when we try to target developmental defects, we could have a totally different therapeutic effect at different stages during development.”
Pouchelon’s team hopes their discovery may serve as a guide for designing future therapeutics to treat brain dysfunction early. “The brain is a wonderful machine whose job is to adapt,” says Dimitri Dumontier, the postdoc in Pouchelon’s lab who co-led this study. “So, when you study neurodevelopmental disorders in adults or even teenagers, it is difficult to identify which mechanisms are causing the symptoms. That is why understanding early milestones of brain development is key.”
The hope is that by figuring out exactly how the brain matures, scientists can rescue this process early. This could help prevent symptoms of neurological disorders like autism from showing up in the first place. After all, the world is difficult enough to navigate as is. Pouchelon and Dumontier’s work could someday help make life easier for countless young people.

Researchers have developed a lightweight fluidic engine to power muscle-mimicking soft robots for use in assistive devices. What sets the new engine apart is its ability to generate significant force without being tethered to an external power source.
“Soft robots that are powered by fluid engines — such as hydraulic or pneumatic action — can be used to mimic the behavior of muscle in ways that rigid robots cannot,” says Hao Su, corresponding author of a paper on the work and an associate professor of mechanical and aerospace engineering at North Carolina State University. “This makes these robots particularly attractive for use in assistive devices that improve people’s ability to move their upper or lower limbs.”
However, most fluid engines are physically connected to an external power source, such as a large air compressor. That significantly limits their utility. And previous fluid engines that were not tethered to external power sources were not able to generate much force, which also limited their utility.
“Our work here addresses both of those challenges,” Su says. “Our fluidic engine is not tethered to an external source but can still generate up to 580 Newtons of force.”
The new engine works by pumping oil into and out of a chamber in a soft robot, causing the soft robot to act as an artificial muscle that is flexing and relaxing. The fluidic engine’s pump is driven by a battery-powered high-torque motor that allows it to generate significant pressure, enabling the artificial muscle to exert significant force. 
In proof-of-concept testing, the researchers not only assessed the amount of force the new engine can generate, but how efficiently the engine converts electrical power into fluidic power.
“We found that we were able to generate an unprecedented amount of force for an untethered engine, while still keeping the weight of the fluidic engine low,” says Antonio Di Lallo, first author of the paper and a postdoctoral researcher at NC State. “And the maximum efficiency of our fluidic engine is higher than previous portable, untethered engines.”
The paper, “Untethered Fluidic Engine for High-Force Soft Wearable Robots,” is published open access in the journal Advanced Intelligent Systems. The paper was co-authored by Shuangyue Yu, a former postdoctoral researcher at NC State; Jie Yin, an associate professor of mechanical and aerospace engineering at NC State; Jonathon Slightam of Sandia National Laboratories; and Grace Gu of the University of California, Berkeley.
This work was done with support from the National Science Foundation under grants 2026622 and 1944655; the National Institute on Disability, Independent Living, and Rehabilitation Research, under grant 90DPGE0011; and Amazon Robotics.

A study at Umeå University, Sweden, provides new clues in the understanding of how antibiotic resistance spreads. The study shows how an enzyme breaks down the bacteria’s protective outer layer, the cell wall, and thus facilitates the transfer of genes for resistance to antibiotics.
“You could say that we are adding a piece of the puzzle to the understanding of how antibiotic resistance spreads between bacteria,” says Ronnie Berntsson, Associate Professor at Umeå University and one of the authors behind the study.
The Umeå researchers have studied Enterococcus faecalis, which is a bacterium that often causes hospital infections, where in many cases treatment with antibiotics no longer bites because the bacteria have developed resistance. These bacteria can also spread the resistance further via the type 4 secretion systems, T4SS. It is a kind of protein complex that acts as a copying device, allowing properties in the form of genetic material to be spread to other bacteria. Resistance to antibiotics is one such trait that can be moved between bacteria with the help of T4SS.
An important part of T4SS is the enzyme PrgK, which breaks down the bacterial cell wall and thus facilitates the transfer of properties between bacteria. This enzyme has three parts or domains, LytM, SLT, and CHAP.
PrgK works like scissors that cut into the bacterial cell wall. Contrary to what the researchers previously thought, it turned out that only the SLT domain was active, but in a different way than expected. The other two domains instead turned out to have an important role in the regulation of the enzyme. The researchers also identified that another T4SS protein, PrgL, binds to PrgK and ensures that it ends up in the right place in the protein machinery.
“The findings are important for continued research into how to prevent T4SS from transferring properties such as resistance to antibiotics to other bacteria,” says Josy ter Beek, Staff scientist at Umeå University.
The study has been conducted through a combination of biochemical analyses of the protein linked to functional studies in vivo, and supplemented with structural studies of PrgK using both X-ray crystallography and AlphaFold modelling.

Antibiotic resistant bacteria are experts in evolving new strategies to avoid being killed by antibiotics.
One such bacterium is Pseudomonas aeruginosa, which is naturally found in soil and water, but also hospitals, nursing homes and similar institutions for persons with weakened immune systems are home for strains of this bacterium. As many P. Aeruginosa strains found in hospitals are resistant to most antibiotics in use, science is forced to constantly search for new ways to kill them.
Now, at team of researchers from Department of Biochemistry and Molecular Biology and Department of Clinical Microbiology, University of Southern Denmark, have discovered a weakness in P. Aeruginosa with the potential to become the target for a new way to attack it. The team has published their findings in the journal Microbiology Spectrum. The authors are Clare Kirkpatrick, Magnus Z. Østergaard, Flemming D. Nielsen and Mette H. Meinfeldt.
Thick and slimy biofilm
The team discovered a mechanism, that reduces the formation of biofilm on the surface of P. Aeruginosa. The formation of sticky, slimy biofilm is a powerful tool used by bacteria to protect themselves against antibiotics — a trick also used by P. Aeruginosa.
“This biofilm can be so thick and gooey that antibiotic cannot penetrate the cell surface and reach its target inside the cell,” said Clare Kirkpatrick, head of research at Department of Biochemistry and Molecular Biology, adding:
“Maybe one day, we could pharmacologically stimulate this mechanism to reduce biofilm development on the surface of P. Aeruginosa.”
Three new genes

Specifically, the researchers worked with three newly discovered genes in a lab-grown strain of P. Aeruginosa. When they overexpressed these genes, they saw a strong reduction of biofilm. Of significance is that the system affected by the genes is part of the P. Aeruginosa core genome, meaning that it is universally found in all the P. Aeruginosa strains sequenced so far.
“Being part of P. Aeruginosa’s core genome, this system has been found in all investigated strains of P. Aeruginosa, including a large variety of strains isolated from patients. So, there is reason to believe that reduction of biofilm via this system should be effective in all known strains of P. Aeruginosa”, said Clare Kirkpatrick.
Bacteria strains can evolve individually and mutate quickly and constantly when they are under pressure. It is not uncommon for patients infected with a P. Aeruginosa strain to initially respond well to antibiotic treatment but then become resistant as the strain evolves resistance during treatment. Strains mutate, but their common core genome does not change.
Stressing the cell wall
In their experiments, the researchers activated the biofilm reducing system by overexpressing genes. But they also discovered that the system is naturally stimulated by cell wall stress.
“So, if we stress the cell wall, it may naturally lead to a reduction in biofilm, making it easier for antibiotic to penetrate the cell wall,” said Clare Kirkpatrick, adding:
“Currently, cell wall-targeted drugs are not widely used against P. Aeruginosa, but perhaps, they could start to be used as additives to help reduce biofilm production and improve access of the existing antibiotics to the cells.”

Bacteria cell wall is very different from human cell wall
When combating infectious bacteria, there are only a limited number of targets to attack. Targets found in both bacterial and human cells cannot be attacked, as the antibiotics would also affect human cells.
Bacterial cells and human cells have some targets in common, such as the process that replicates DNA and the processes controlling basic glucose metabolism or respiration in cells.
Among the targets unique to bacteria are various protein functions and also the bacterial cell wall is considered a suitable target, as it is very different from the human cell wall.

Multiple myeloma is one of the most common forms of cancer of the immune cells in the bone marrow. It is considered incurable. Even when patients respond to treatment at first, the cancer comes back. To be able to intervene faster and on a more targeted basis, researchers at Charité — Universitätsmedizin Berlin, the Berlin Institute of Health at Charité (BIH), and the Max Delbrück Center teamed up with other partners for a comprehensive study of this disease at the molecular level. The team now describes how highly aggressive types of tumors can be detected early on in an article published in the journal Nature Cancer.* They show how changes in genetic material affect the protein profile of the tumor cells, and thus the mechanisms involved in the disease.
Multiple myeloma is a form of cancer in which the immune cells in the bone marrow, known as plasma cells, mutate and become cancerous. Plasma cells are responsible for producing antibodies. All humans have many different kinds of plasma cells that form large numbers of different antibodies. This allows the body to recognize and fight various pathogens. In multiple myeloma, a single plasma cell mutates into a tumor cell. That cell reproduces unchecked, forming a monoclonal cell population. This means many cells are formed, all of them exactly the same and genetically identical at first. The mutated cells often also produce large volumes of antibodies or fragments of them — but they do not function properly.
Over the course of the disease, most patients develop tumors at various locations in the bone marrow, hence the “multiple” in the disease’s name. Immunodeficiency, kidney failure, bone loss, and bone fractures are just some of the consequences of this uncontrolled cell growth. Despite advances in treatment and the introduction of new gene and cell therapies, there is no cure for multiple myeloma at present. With this issue in mind, a team of researchers led by Jan Krönke from the Department of Hematology, Oncology and Cancer Immunology at Charité and Dr. Philipp Mertins, head of the Proteomics technology platform of the Max Delbrück Center and BIH, set out in search of new approaches to diagnosis and treatment.
What path does the tumor take?
No two cases of cancer are alike, and multiple myeloma is no exception. Tumors develop differently in different individuals, including at different rates. This makes it more difficult to predict how the disease will progress and choose the optimum treatment. While the mutated plasma cells do not spread much in some cases, in others they are extremely aggressive, leading to a poor prognosis.
But what causes so much divergence in the course of multiple myeloma? In cooperation with protein analysis experts from the Max Delbrück Center and BIH, the researchers conducted a detailed study of genetic and molecular changes occurring in the tumor cells in a group of more than one hundred patients. The study included data from patients in the German Multiple Myeloma Study Group (DSMM), which is coordinated by the University Hospital of Würzburg. This allowed the researchers to include clinical data on patients who had received standardized treatment over a period of eight years or more following initial diagnosis.
Systems medicine and big data
While changes in the genome and their effects on the proteome are already well described for other types of cancer, this is the first detailed proteo-genomic study of multiple myeloma. “Genetic data alone is insufficient to explain the mechanisms involved in this disease,” Mertins says. “We wanted to know the consequences of genetic changes at the protein level and compare this molecular biology data against the actual course of the disease in patients.” The team was supported in collecting and analyzing the large volumes of data by experts at Charité, BIH, and the German Cancer Consortium (DKTK).

Cutting-edge mass spectrometry methods made it possible to map the protein profile of mutated plasma cells and compare it against that of healthy plasma cells in people without the disease. The researchers found that both genetic changes and changes in signaling pathways lead to uncontrolled activation of cancer cells. Regulatory processes at the protein level had the stronger influence. The researchers identified a protein constellation that suggests the disease will take a particularly aggressive course, regardless of other known risk factors.
Unlocking new therapies
“Our findings will help subcategorize patients more effectively going forward, personalizing their treatment,” Krönke concludes. “We’ve identified key proteins and signaling pathways that can serve as the basis for even more effective, better tolerated treatments for multiple myeloma, for example for immune therapies such as CAR T-cell therapy.” In further steps, the researchers plan to study which of the target structures they have identified are in fact good candidates for new therapeutic approaches.
The study is a crucial resource for research and applied development, says Dr. Evelyn Ramberger, first author of the study: “To make the complex data set manageable, we programmed an interactive, freely available online tool.” This has given cancer researchers easy access to the results, so they can use the information to develop new therapies and tests to help guide treatment. For example, it may be possible to treat patients with an especially aggressive form of multiple myeloma with more intensive therapies right at the outset.
Mass spectrometry
Mass spectrometry is a technique for analyzing the mass of molecules and atoms. The substance to be analyzed is ionized and converted to a gas phase. The ions formed are sharply accelerated using an electric field and then sorted by mass-to-charge ratio in the mass spectrometer’s analytical unit. The mass spectrum of a substance provides information on its molecular composition. Mass spectrometry is therefore useful for identifying, characterizing, and quantifying a large number of biomolecules, such as proteins, metabolites, sugars, and fats, which may behave differently depending on the disease and the individual organism.

Cancer treatments often cause nerve damage that can lead to long-lasting symptoms. Medication has proven ineffective in these cases. A sports scientist at the University of Basel, together with an interdisciplinary team from Germany, has now shown that simple exercises can prevent nerve damage.
Cancer therapies have improved over the years. It is no longer just about sheer survival: quality of life after recovery is gaining more importance.
Unfortunately, many cancer medications, from chemotherapy to modern immunotherapies, attack the nerves as well as the tumor cells. Some therapies, such as oxaliplatin or vinca alkaloids, leave 70 to 90 percent of patients complaining of pain, balance issues, or feelings of numbness, burning or tingling. These symptoms can be very debilitating. They can disappear following cancer treatment, but in around 50 percent they become chronic. Specialists call it chemotherapy-induced peripheral neuropathy, or CIPN for short.
A research team led by sports scientist Dr. Fiona Streckmann from the University of Basel and the German Sport University Cologne has now shown that specific exercise, concomitant to cancer therapy, can prevent nerve damage in many cases. The researchers have reported their findings in the journal JAMA Internal Medicine.
Exercise alongside chemo
The study involved 158 cancer patients, both male and female, who were receiving treatment either with oxaliplatin or vinca-alkaloids. The researchers divided the patients at random into three groups. The first was a control group, whose members received standard care. The other two groups completed exercise sessions twice a week for the duration of their chemotherapy, with each session lasting between 15 and 30 minutes. One of these groups carried out exercises that focused primarily on balancing on an increasingly unstable surface. The other group trained on a vibration plate.
Regular examinations over the next five years showed that in the control group around twice as many participants developed CIPN as in either of the exercise groups. In other words, the exercises undertaken alongside chemotherapy were able to reduce the incidence of nerve damage by 50 to 70 percent. In addition, they increased the patients’ subjectively perceived quality of life, made it less necessary to reduce their dose of cancer medications, and reduced mortality in the five years following chemotherapy.

The participants receiving vinca-alkaloids and performing sensorimotor training, had the largest benefit.
Ineffective medications
A lot of money has been invested over the years in reducing the incidence of CIPN, explains Streckmann. “This side effect has a direct influence on clinical treatment: for example, patients may not be able to receive the planned number of chemotherapy cycles that they actually need, the dosage of neurotoxic agents in the chemotherapy may have to be reduced, or their treatment may have to be terminated.”
Despite the investments made, there is no effective pharmacological treatment to date: various studies have shown that medications can neither prevent nor reverse this nerve damage. However, according to the latest estimates, USD 17,000 are spent per patient every year in the USA on treating nerve damage associated with chemotherapy. Streckmann’s assumption is that “doctors prescribe medications despite everything, because patients’ level of suffering is so high.”
Study ongoing in children’s hospitals
In contrast, the sports scientist emphasizes, the positive effect of exercise has been substantiated, and this treatment is very cheap in comparison. At the moment she and her team are working on guidelines for hospitals, so that they can integrate the exercises into clinical practice as supportive therapy. In addition, since 2023 a study has been ongoing in six children’s hospitals in Germany and Switzerland (PrepAIR), which is intended prevent sensory and motor dysfunctions in children receiving neurotoxic chemotherapy.
“The potential of physical activity is hugely underestimated,” says Fiona Streckmann. She very much hopes that the results of the newly published study will lead to more sports therapists being employed in hospitals, in order to better exploit this potential.

New UCSF study shows that suppressing a protein turns ordinary fat into a calorie burner and may explain why drug trials attempting the feat haven’t been successful.
Researchers at UC San Francisco have figured out how to turn ordinary white fat cells, which store calories, into beige fat cells that burn calories to maintain body temperature.
The discovery could open the door to developing a new class of weight-loss drugs and may explain why clinical trials of related therapies have not been successful.
Until now, researchers believed creating beige fat might require starting from stem cells. The new study published July 1 in the Journal of Clinical Investigation, showed that ordinary white fat cells can be converted into beige fat simply by limiting production of a protein.
“A lot of people thought this wasn’t feasible,” said Brian Feldman, MD, PhD, the Walter L. Miller, MD Distinguished Professor in Pediatric Endocrinology and senior author of the study. “We showed not only that this approach works to turn these white fat cells into beige ones, but also that the bar to doing so isn’t as high as we’d thought.”
A fat transformation
Many mammals have three “shades” of fat cells: white, brown and beige. White fat serves as energy reserves for the body, while brown fat cells burn energy to release heat, which helps maintain body temperature.

Beige fat cells combine these characteristics. They burn energy, and unlike brown fat cells, which grow in clusters, beige fat cells are embedded throughout white fat deposits.
Humans and many other mammals are born with brown fat deposits that help them maintain body temperature after birth. But, while a human baby’s brown fat disappears in the first year of life, beige fat persists.
Humans can naturally turn white fat cells into beige ones in response to diet or a cold environment. Scientists tried to mimic this by coaxing stem cells into becoming mature beige fat cells.
But stem cells are rare, and Feldman wanted to find a switch he could flip to turn white fat cells directly into beige ones.
“For most of us, white fat cells are not rare and we’re happy to part with some of them,” he said.
Of mice and humans
Feldman knew from his earlier experiments that a protein called KLF-15 plays a role in metabolism and the function of fat cells.

With postdoctoral scholar Liang Li, PhD, Feldman decided to investigate how the protein functioned in mice, which retain brown fat throughout their lives. They found that KLF-15 was much less abundant in white fat cells than in brown or beige fat cells.
When they then bred mice with white fat cells that lacked KLF-15, the mice converted them from white to beige. Not only could the fat cells switch from one form into another, but without the protein, the default setting appeared to be beige.
The researchers then looked at how KLF-15 exerts this influence. They cultured human fat cells and found that the protein controls the abundance of a receptor called Adrb1, which helps maintain energy balance.
Scientists knew that stimulating a related receptor, Adrb3, caused mice to lose weight. But human trials of drugs that act on this receptor have had disappointing results.
A different drug targeting the Adrb1 receptor in humans is more likely to work, according to Feldman, and it could have significant advantages over the new, injectable weight-loss drugs that are aimed at suppressing appetite and blood sugar.
Feldman’s approach might avoid side effects like nausea because its activity would be limited to fat deposits, rather than affecting the brain. And the effects would be long lasting, because fat cells are relatively long-lived.
“We’re certainly not at the finish line, but we’re close enough that you can clearly see how these discoveries could have a big impact on treating obesity,” he said.
Liang Li is also an author of this study.
This work was funded by NIH grant R01DK132404.

Our bodies are inhabited by trillions of microorganisms, with specific microbes unique to each individual. Through experimentation, scientists have pinpointed certain factors that account for variation in the gut: diet, living conditions, exercise and maternal line. Now, scientists at University of California San Diego have discovered another factor that affects the composition of the gut microbiome: time of day. In fact, the scientists have found that time of day is such an important factor that they’re calling on the National Institutes of Health (NIH) to require researchers to report it in their papers.
In new work published in Nature Metabolism, the scientists report that daily fluctuations in the gut alter the microbiome so significantly that different bugs populate it in the morning and in the evening. That means that a researcher analyzing a stool sample collected at breakfast will reach radically different conclusions from a researcher analyzing a stool sample collected right before dinner. The UC San Diego scientists propose that this variability is keeping gut microbiome researchers from being able to replicate each other’s experiments.
“Unexplained variability and lack of replicability may be due to the fact that the microbiome oscillates throughout the day, with different populations of microbes dominating at different times,” said Amir Zarrinpar, M.D., Ph.D., gastroenterologist and associate professor of medicine at UC San Diego School of Medicine and senior author on the study. “We found that when a sample is taken can dramatically affect which microbes were present and the conclusions the scientists drew about the disease they were studying.”
Scientists conduct experiments for many reasons. The traditional reason is to answer a specific question, but another reason is to make a discovery or arrive at a scientific truth that others can replicate with their own experiments. In gut microbiome research, scientists collect stool samples to discover which microorganisms are present, and in what amount. Then, they link those changes to disease processes.
For this study, the team compared computer analyses of previously published studies, including their own. They discovered that changes in the microbiome were so pronounced over time that they affected the results as much as diet did. “We found that in as little as four hours after a mouse eats breakfast, nearly 80 percent of its microbiome is different,” said Zarrinpar. Analyzing the conclusions drawn in the studies, Zarrinpar and his team found that results and conclusions depended heavily on when the researchers collected the samples.
Zarrinpar was inspired to conduct this study by a conversation he had with a colleague. “He told me that a postdoc in his lab took over an experiment that had been started by someone else. The postdoc couldn’t replicate any of the previous trainee’s findings. That made him question his predecessor’s research,” said Zarrinpar. “Then the postdoc realized that a bacteria that was incredibly pervasive in his findings was one that appears late in the day. He went back to his lab and saw that the previous trainee liked to collect samples in the morning, while he himself collected samples before going home. That’s why he couldn’t replicate the first trainee’s findings.”
Being able to reproduce the results of a previous experiment — replicability — is a key element in knowing whether a finding reliably represents new knowledge about reality or is simply an artifact of the experiment. Microbiome research is currently experiencing a replicability crisis, in part because of the interdisciplinary nature of the field, the complicated relationship between microorganisms and their hosts, and the difficulty of controlling so many variables.

Zarrinpar believes that his team’s newest findings about the significance of timing can help fix the replicability crisis in microbiome research. He explains, “If we’re ever going to be able to communicate to each other about our science and what we think is going on in an effective way, then we need to understand that if you got different results than I did, maybe that could be due to the time that we’re collecting samples or not. Right now, you can’t even tell.”
According to Zarrinpar, scientists in other fields, such as circadian biologists, have also been lobbying the NIH to be stricter about the need to report timing of sample collections. Zarrinpar is hoping that publication of this paper will convince more scientists — and the people who fund and publish their research — of the significance of timing and its possible effect on other fields as well, such as metabolism research.
Zarrinpar’s next steps involve advocating for standardized guidelines that ensure consistency in microbiome sample collection times and methodology. “This will likely involve collaboration with other researchers, funding agencies and journal editors to promote the adoption of such standards,” he said. His next paper focuses on understanding the impact of timing in humans — a variable that’s much more difficult to control.
This research was funded in part by the National Institutes of Health, the Soros Foundation, and the American Hospital Association.
Co-authors on the study include: Celeste Allaband, Amulya Lingaraju, Stephany Flores Ramos, Tanya Kumar, Haniyeh Javaheri, Maria D. Tiu, Ana Carolina Dantas Machado, Roland A. Richter, Emmanuel Elijah, Gabriel G. Haddad, Pieter C. Dorrestein, Rob Knight of University of California San Diego, and Vanessa A. Leone, University of Wisconsin-Madison.

Researchers at Karolinska Institutet in Sweden have developed nanorobots that kill cancer cells in mice. The robot’s weapon is hidden in a nanostructure and is exposed only in the tumour microenvironment, sparing healthy cells. The study is published in the journal Nature Nanotechnology.
The research group at Karolinska Institutet has previously developed structures that can organise so-called death receptors on the surface of cells, leading to cell death. The structures exhibit six peptides (amino acid chains) assembled in a hexagonal pattern.
“This hexagonal nanopattern of peptides becomes a lethal weapon,” explains Professor Björn Högberg at the Department of Medical Biochemistry and Biophysics, Karolinska Institutet, who led the study. “If you were to administer it as a drug, it would indiscriminately start killing cells in the body, which would not be good. To get around this problem, we have hidden the weapon inside a nanostructure built from DNA.”
Created a ‘kill switch’
The art of building nanoscale structures using DNA as a building material is called DNA origami and is something Björn Högberg’s research team has been working on for many years. Now they have used the technique to create a ‘kill switch’ that is activated under the right conditions.
“We have managed to hide the weapon in such a way that it can only be exposed in the environment found in and around a solid tumour,” he says. “This means that we have created a type of nanorobot that can specifically target and kill cancer cells.”
The key is the low pH, or acidic microenvironment that usually surrounds cancer cells, which activates the nanorobot’s weapon. In cell analyses in test tubes, the researchers were able to show that the peptide weapon is hidden inside the nanostructure at a normal pH of 7.4, but that it has a drastic cell-killing effect when the pH drops to 6.5.

Reduced tumour growth
They then tested injecting the nanorobot into mice with breast cancer tumours. This resulted in a 70 per cent reduction in tumour growth compared to mice given an inactive version of the nanorobot.
“We now need to investigate whether this works in more advanced cancer models that more closely resemble the real human disease,” says the study’s first author Yang Wang, a researcher at the Department of Medical Biochemistry and Biophysics, Karolinska Institutet. “We also need to find out what side effects the method has before it can be tested on humans.”
The researchers also plan to investigate whether it is possible to make the nanorobot more targeted by placing proteins or peptides on its surface that specifically bind to certain types of cancer.

Genes can indirectly influence the age at which girls have their first period by accelerating weight gain in childhood, a known risk factor for early puberty, a Cambridge-led study has found. Other genes can directly affect age of puberty, some with profound effects.
In the largest study of its kind to date, an international team led by researchers at the Medical Research Council (MRC) Epidemiology Unit, University of Cambridge, studied the DNA of around 800,000 women from Europe, North America, China, Japan, and Korea.
Published today in Nature Genetics, the researchers found more than 1,000 variants — small changes in DNA — that influence the age of first menstrual period. Around 600 of these variants were observed for the first time.
The age at which girls hit puberty and start having periods normally occurs between ages 10 to 15, though this has been getting earlier and earlier in recent decades. The reasons for this are not fully understood. Early puberty is linked with increased risk of a number of diseases in later life, including type 2 diabetes, cardiovascular disease, and certain cancers. Later puberty on the other hand, has been linked to improved health in adulthood and a longer lifespan.
Just under half (45%) of the discovered genetic variants affected puberty indirectly, by increasing weight gain in early childhood.
Corresponding author Professor John Perry said: “Many of the genes we’ve found influence early puberty by first accelerating weight gain in infants and young children. This can then lead to potentially serious health problems in later life, as having earlier puberty leads to higher rates of overweight and obesity in adulthood.”
Previous work by the team — together with researchers at Cambridge’s MRC Metabolic Diseases Unit — showed that a receptor in the brain, known as MC3R, detects the nutritional state of the body and regulates the timing of puberty and rate of growth in children, providing a mechanism by which this occurs. Other identified genes appeared to be acting in the brain to control the release of reproductive hormones.

The scientists also analysed rare genetic variants that are carried by very few people, but which can have large effects on puberty. For example, they found that one in 3,800 women carry variants in the gene ZNF483, which caused these women to experience puberty on average, 1.3 years later.
Dr Katherine Kentistou, lead study investigator, added: “This is the first time we’ve ever been able to analyse rare genetic variants at this scale. We have identified six genes which all profoundly affect the timing of puberty. While these genes were discovered in girls, they often have the same impact on the timing of puberty in boys. The new mechanisms we describe could form the basis of interventions for individuals at risk of early puberty and obesity.”
The researchers also generated a genetic score that predicted whether a girl was likely to hit puberty very early or very late. Girls with the highest 1% of this genetic score were 11 times more likely to have extremely delayed puberty — that is, after age 15 years. On the other hand, girls with the lowest 1% genetic score were 14 times more likely to have extremely early puberty — before age 10.
Senior author and paediatrician Professor Ken Ong said: “In the future, we may be able to use these genetic scores in the clinic to identify those girls whose puberty will come very early or very late. The NHS is already trialling whole genome sequencing at birth, and this would give us the genetic information we need to make this possible.
“Children who present in the NHS with very early puberty — at age seven or eight — are offered puberty blockers to delay it. But age of puberty is a continuum, and if they miss this threshold, there’s currently nothing we have to offer. We need other interventions, whether that’s oral medication or a behavioural approach, to help. This could be important for their health when they grow up.”
The research was supported by the Medical Research Council and included data from the UK Biobank.