Publisher Health

The incidence of primary involuntary childlessness, the rate of women seeking treatment for infertility, as well as the success rate of assisted reproductive technology all increased in birth cohorts studied from 1916 to 1975, according to a new study published this week in the open-access journal PLOS ONE by Finn Egil Skjeldestad of the Arctic University of Norway.
There have been tremendous advances in assisted reproductive technologies (ARTs) over the past 50 years. In the new study, Dr. Skjeldestad analyzed data on 11,064 women born between 1916 and 1975 who took part in the 2015-2016 Tromsø survey, a large population-based survey that invites all residents of Tromsø, Norway to participate in regular questionnaires about their sociodemographics and health.
The analysis found that 6.0% of women born in 1956-75 had primary involuntary childlessness (95% CI 5.4-6.6%), compared to only 3.7% of those born in 1916-55 (95% CI 3.2-4.3%). Similarly, 10% of women born in 1966-75 had secondary infertility, defined as infertility after having at least one naturally conceived child, compared to 6 to 7% of women in the earlier birth year cohorts.
Along with these increases, more women in the younger birth cohorts reported the use of ART. The success of ART also increased over time, reaching 58% for primary and 46% for secondary infertility for the 1966-75 birth cohort. Notably, ART can be credited with comprising 2.0% of the population growth for the 1956-65 cohort and 3.3% of population growth for the 1966-75 cohort, but its effect is negligible in older cohorts. Meanwhile, the rate of voluntary childlessness grew from 5-6% in the 1916-1955 cohort to 9-10% in the 1956-75 cohort.
Dr. Skjeldestad concludes that the data offer valuable insight into infertility trends and ART outcomes among women of reproductive age during much of the last century.

Prosthetic limbs are the most common solution to replace a lost extremity. However, they are hard to control and often unreliable with only a couple of movements available. Remnant muscles in the residual limb are the preferred source of control for bionic hands. This is because patients can contract muscles at will, and the electrical activity generated by the contractions can be used to tell the prosthetic hand what to do, for instance, open or close. A major problem at higher amputation levels, such as above the elbow, is that not many muscles remain to command the many robotic joints needed to truly restore the function of an arm and hand.
A multidisciplinary team of surgeons and engineers has circumvented this problem by reconfiguring the residual limb and integrating sensors and a skeletal implant to connect with a prosthesis electrically and mechanically. By dissecting the peripheral nerves and redistributing them to new muscle targets used as biological amplifiers, the bionic prosthesis can now access much more information so the user can command many robotic joints at will (video: https://youtu.be/h1N-vKku0hg).
The research was led by Professor Max Ortiz Catalan, Founding Director of the Center for Bionics and Pain Research (CBPR) in Sweden, Head of Neural Prosthetics Research at the Bionics Institute in Australia, and Professor of Bionics at Chalmers University of Technology in Sweden.
“In this article, we show that rewiring nerves to different muscle targets in a distributed and concurrent manner is not only possible but also conducive to improved prosthetic control. A key feature of our work is that we have the possibility to clinically implement more refine surgical procedures and embed sensors in the neuromuscular constructs at the time of the surgery, which we then connect to the electronic system of the prosthesis via an osseointegrated interface. A.I. algorithms take care of the rest.”
Prosthetic limbs are commonly attached to the body by a socket that compresses the residual limb causing discomfort and is mechanically unstable. An alternative to socket attachment is to use a titanium implant placed within the residual bone which becomes strongly anchored — this is known as osseointegration. Such skeletal attachment allows for comfortable and more efficient mechanical connection of the prosthesis to the body.
“It is rewarding to see that our cutting-edge surgical and engineering innovation can provide such a high level of functionality for an individual with an arm amputation. This achievement is based on over 30 years of gradual development of the concept, in which I am proud to have contributed” comments Dr. Rickard Brånemark, research affiliate at MIT, associate professor at Gothenburg University, CEO of Integrum, a leading expert on osseointegration for limb prostheses, who conducted the implantation of the interface.
The surgery took place at the Sahlgrenska University Hospital, Sweden, where CBPR is located. The neuromuscular reconstruction procedure was conducted by Dr. Paolo Sassu, who also led the first hand transplantation performed in Scandinavia.
“The incredible journey we have undertaken together with the bionic engineers at CBPR has allowed us to combine new microsurgical techniques with sophisticated implanted electrodes that provide single-finger control of a prosthetic arm as well as sensory feedback. Patients who have suffered from an arm amputation might now see a brighter future,” says Dr. Sassu, who is presently working at the Istituto Ortopedico Rizzoli in Italy.
The Science Translational Medicine article illustrates how the transferred nerves progressively connected to their new hosting muscles. Once the innervation process had advanced enough, the researchers connected them to the prosthesis so the patient could control every finger of a prosthetic hand as if it would be his own (video: https://youtu.be/FdDdZQg58kc). The researchers also demonstrated how the system respond in activities of the daily life (video: https://youtu.be/yC24WRoGIe8) and are currently in the process of further improving the controllability of the bionic hand.

For the first time, researchers have developed a model to estimate how much energy the original colonizers of New Zealand expended to maintain their body temperatures on the cold, harrowing ocean journey from Southeast Asia.
Results showed that people making the first voyages from Tahiti to New Zealand in sailing canoes would expend 3.3 to 4.8 times more energy on thermoregulation — the technical term for maintaining body temperature — than those making a trip of similar length to Hawaii.
The ocean route to New Zealand required much more energy for thermoregulation because it went through harsher and colder conditions than the one to Hawaii, said Alvaro Montenegro, lead author of the study and associate professor of geography at The Ohio State University.
The findings help provide additional evidence supporting the long-standing theory of why Polynesians of today have a distinctive body type — relatively larger, heavier, bulkier — that is more often found in populations that live in higher latitudes with colder climates.
“It has been long hypothesized that the first trips to New Zealand were much harder on the body of settlers than trips of similar lengths to places like Hawaii,” Montenegro said.
“We were able to put together a model to actually measure how much more energy for thermoregulation it would take for people to get there — and show why larger, heavier people would have been more likely to survive the trip. That’s one reason why their descendants today may have the body types they do.”
The study was published today (July 12, 2023) in the journal PLOS ONE.

Although much of East Polynesia is tropical, the southern third, including New Zealand, ranges from a warm- to cool-temperate climate. Researchers say that may be one of the reasons it was one of the last places on Earth to become inhabited. The first people arrived in New Zealand about the 14th century.
“The basic question is how difficult would it be on human physiology to sail out of the tropics on these long-distance colonizing voyages through much harsher environmental conditions than they were used to?” Montenegro said.
Researchers believe that these original settlers used double-hulled sailing canoes that probably each had at most a few dozen voyagers on board.
Montenegro and colleagues had previously developed a voyage simulation model that estimates how far these boats would travel each day based on winds and currents. In this study, the researchers used that model combined with likely environmental conditions that voyagers would encounter, including air temperatures and wind.
To evaluate how body size would affect energy use for thermoregulation on these voyages, the researchers used female and male bodies of three different types. One body type resembled Polynesians of today, a second one was of a higher weight, and the third type had higher body weight and additional subcutaneous fat layer thickness.

The researchers estimated how much energy it would take travelers to maintain their body temperature sailing from Tahiti to New Zealand and compared that to travelers going to Hawaii, which they estimated would take about 23 days, similar to the 25-day trip to New Zealand.
The model the researchers used did not account for energy used by physical activity, which of course would be an additional need for the voyagers.
Results showed that the trip to New Zealand would take significantly more energy than the trip to Hawaii, Montenegro said.
Based on a summer trip (which would require less energy than a winter trip), each traveler to New Zealand would require an average of an extra 965 calories a day compared to those going to Hawaii to maintain their body temperature.
If this deficit was completely made up by burning fat, those going to New Zealand would lose an average of an extra 5.9 pounds at the end of a 25-day trip. If the difference was compensated just by use of muscle mass, the whole trip extra weight loss would be about 13.3 pounds.
Model calculations showed that travelers with a larger body size experienced lower heat loss, and so had an energy advantage compared to those of smaller body sizes. The advantage was greater for females.
“The trip would be difficult under any circumstances, but our results showed that people of larger body size would have had an advantage under the harsh conditions they faced,” Montenegro said.
These findings line up with the larger bodies of Polynesian populations today, including the fact that females are about 31% heavier, and males 24% heavier, than populations to their west.
“Our analysis can’t definitively prove that the size differences we see in Polynesia today are the result of larger people being more likely to survive the original trips and colonizing the region, but it certainly is consistent with that fact,” he said.
Other authors on the study were Alexandra Niclou of the Pennington Biomedical Research Center and University of Notre Dame; Atholl Anderson of Australian National University and University of Canterbury; Scott Fitzpatrick of the University of Oregon; and Cara Ocobock of the University of Notre Dame.

Companion robots enhanced with artificial intelligence may one day help alleviate the loneliness epidemic, suggests a new report from researchers at Auckland, Duke, and Cornell Universities.
Their report, appearing in the July 12 issue of Science Robotics,maps some of the ethical considerations for governments, policy makers, technologists, and clinicians, and urges stakeholders to come together to rapidly develop guidelines for trust, agency, engagement, and real-world efficacy.
It also proposes a new way to measure whether a companion robot is helping someone.
“Right now, all the evidence points to having a real friend as the best solution,” said Murali Doraiswamy, MBBS, FRCP, professor of Psychiatry and Geriatrics at Duke University and member of the Duke Institute for Brain Sciences. “But until society prioritizes social connectedness and eldercare, robots are a solution for the millions of isolated people who have no other solutions.”
The number of Americans with no close friends has quadrupled since 1990, according to the Survey Center on American Life. Increased loneliness and social isolation may affect a third of the world population, and come with serious health consequences, such as increased risk for mental illness, obesity, dementia, and early death. Loneliness may even be as pernicious a health factor as smoking cigarettes, according to the U.S. Surgeon General Vivek H. Murthy, M.D.
While it is increasingly difficult to make new friends as an adult to help offset loneliness, making a companion robot to support socially isolated older adults may prove to be a promising solution.

“AI presents exciting opportunities to give companion robots greater skills to build social connection,” said Elizabeth Broadbent, Ph.D., professor of Psychological Medicine at Waipapa Taumata Rau, University of Auckland. “But we need to be careful to build in rules to ensure they are moral and trustworthy.”
Social robots like the ElliQ have had thousands of interactions with human users, nearly half related to simple companionship, including company over a cup of tea or coffee. A growing body of research on companion robots suggests they can reduce stress and loneliness and can help older people remain healthy and active in their homes.
Newer robots embedded with advanced AI programs may foster stronger social connections with humans than earlier generations of robots. Generative AI like ChatGPT, which is based on large language models, allows robots to engage in more spontaneous conversations, and even mimic the voices of old friends and loved ones who have passed away.
Doctors are mostly on board, too, the authors point out. A Sermo survey of 307 care providers across Europe and the United States showed that 69% of physicians agreed that social robots could provide companionship, relieve isolation, and potentially improve patients’ mental health. Seventy percent of doctors also felt insurance companies should cover the cost of companion robots if they prove to be effective friendship supplement. How to measure a robot’s impact, though, remains tricky.
This lack of measurability highlights the need to develop patient-rated outcome measures, such as the one being developed by the authors. The “Companion Robot Impact Scale” (Co-Bot-I-7) aims to establish the impact on physical health and loneliness, and is showing that companion machines might already be proving effective.
Early results from Broadbent’s lab, for example, find that amiable androids help reduce stress and even promote skin healing after a minor wound.
“With the right ethical guidelines,” the authors conclude in their report, “we may be able to build on current work to use robots to create a healthier society.”
In addition to Dr. Doraiswamy and Professor Broadbent, study authors include Mark Billinghurst, Ph.D., and Samantha Boardman, M.D.
Professor Broadbent and Dr. Doraiswamy have served as advisors to Sermo and technology companies. Dr. Doraiswamy, Professor Broadbent, and Dr. Boardman are co-developers of the Co-Bot-I-7 scale.

A bacterium that causes a disease called scrub typhus — a disease not previously reported in the United States — has been detected in North Carolina, according to a new study by researchers at North Carolina State University and UNC-Greensboro.
The researchers stress that scrub typhus, which can cause fever, headache and body aches — and can be fatal if left untreated by antibiotics — has not yet been detected in animals or people in the state.
The NC State researchers detected the bacterium — the genus is Orientia in the family Rickettsiaceae — at a high frequency while testing free living, larval (ready to bite) trombiculid mites, commonly called chiggers, in several different recreational parks in North Carolina.
“We wanted to see if chiggers in the United States carried Orientia,” said Loganathan Ponnusamy, an NC State principal research scholar in entomology and co-corresponding author of a paper that describes the research. “We haven’t in the past had the diagnostic tools to test for this specific bacterium at the genus level.”
“We set a black tile on the ground in 10 different North Carolina state parks and picked up chiggers as they crossed the tile. Microbiome studies allowed us to characterize all the bacteria in the chiggers. One park showed a 90% positivity rate for the bacterium (nine out of 10 chiggers captured); another showed an 80% positivity rate (eight of 10 chiggers captured). Other parks showed positivity rates of just 10%.”
Trombiculid mites are only parasitic in their larval stage. They search for vertebrate hosts — including humans — to bite, Ponnusamy says.

“Chiggers can spread bacteria to people or rodents when they bite but can also pass bacteria to future generations of mites through their eggs,” he added.
The researchers say that scrub typhus presents symptoms similar to those of Rocky Mountain spotted fever, a disease generally ascribed to tick bites.
Scrub typhus is found more commonly in Asia and the Pacific, but in recent years has been detected in Africa and the Middle East. It is uncertain whether spread is caused by people or goods carrying chiggers from one place to another.
“We don’t know if this is a recent introduction into the state or if the bacterium has been here for years,” said R. Michael Roe, William Neal Reynolds Distinguished Professor of Entomology at NC State and co-author of the paper. “We also don’t know if the infected chiggers found in North Carolina actually will cause disease; this has to be determined in future work.”
“We also don’t have information about whether the chigger infection rate is decreasing or increasing,” said Kaiying Chen, a postdoctoral research scholar at NC State and lead author of the paper.
The NC State and UNC-Greensboro researchers are resampling chiggers in the recreational park sites to see if the reported findings remain consistent.
The paper appears in the journal Emerging Infectious Diseases. Other co-authors include Nicholas V. Travanty and Charles S. Apperson from North Carolina State University; Reuben Garshong and Gideon Wasserberg from the University of North Carolina Greensboro; and Dac Crossley from the Georgia Museum of Natural History.
Funding was provided by a grant from the National Institutes of Health, National Institute of Allergy and Infectious Diseases (grant no. 1R03AI166406-01); a grant from the Southeast Center for Agricultural Health and Injury Prevention, and from the Department of the Army, U.S. Army Contracting Command, Aberdeen Proving Ground, Natick Contracting Division, Ft Detrick MD. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the position or the policy of the Government and no official endorsement should be inferred.

Schistosomiasis, a parasitic disease that causes organ damage and death, affected more than 250 million people worldwide in 2021, according to the World Health Organization.
One of the world’s most burdensome neglected tropical diseases, schistosomiasis occurs when worms are transmitted from freshwater snails to humans. The snails thrive in water with plants and algae that proliferate in areas of agricultural runoff containing fertilizer. People become infected during routine activities in infested water.
Researchers from the University of Notre Dame, in a study recently published in Nature, found that removing invasive vegetation at water access points in and around several Senegalese villages reduced rates of schistosomiasis by almost a third. As a bonus, the removed vegetation can also be used for compost and livestock feed.
“Disease, food, energy, water, sustainability and poverty challenges intersect in many ways, but are typically addressed independently,” said lead author Jason Rohr, the Ludmilla F., Stephen J. and Robert T. Galla College Professor and Department Chair in the Department of Biological Sciences at the University of Notre Dame. “We sought to break down these silos and identify win-win solutions, while demonstrating their cost effectiveness so that residents would hopefully adopt them widely.”
Rohr and his team spent seven years on the project, with research conducted in 23 villages and clinical trials in 16. They found that villages with substantial fertilizer use had more submerged vegetation. These villages had more snails and a higher prevalence of schistosomiasis infection in children, said Rohr, who is affiliated with the Notre Dame Environmental Change Initiative and the Eck Institute for Global Health.
Researchers hypothesized that removing vegetation could reduce infections while providing greater access to the open water that is crucial for daily activities and recreation. So, they conducted a three-year randomized controlled trial in 16 communities, where children were treated for their infections and the researchers removed more than 400 metric tons of vegetation in water access points from half the villages. These removals resulted in a decline in snail abundance as well as schistosomiasis infection rates being nearly a third lower than those observed in control villages.

Rohr’s team also tried to profitably improve food production by partly closing the nutrient loop, returning nutrients captured in the removed plants back to agriculture. So, they worked with local farmers to compost the vegetation for use on pepper and onion plants, increasing their yields, and demonstrated that the vegetation could be effectively used as cattle, sheep and donkey feed. Alexandra “Lexi” Sack, who worked as a postdoctoral researcher in Rohr’s lab from 2021 to 2023, assisted Senegal’s in-country team with the care and design of the sheep-feeding trials, and performed much of the analysis of the vegetation removal results.
“This is important work because it encompasses many different disciplines by combining schistosomiasis prevention and food security,” Sack said. “Often these interventions are separate when the neglected tropical diseases, which includes schistosomiasis, are contributing both to and resulting from poverty.”
With the expertise of co-authors Christopher B. Barrett, an economist at Cornell University, and Molly Doruska, a doctoral student also at Cornell, the research team demonstrated that the benefits of removing the vegetation and using it in agriculture were nearly nine times higher than the costs.
“We took this public nuisance, which is reducing health, and converted it into a private good that improves income,” Rohr said.
The team was also able to illustrate how to scale the project using artificial intelligence and satellite imagery to identify snail habitat and thus hotspots for schistosomiasis, which will allow them to target their intervention training to areas that need it the most.

Villagers helped with removing vegetation once they understood the public health benefits of the intervention, but in the long run, relying on voluntary labor may not be as effective as the researchers removing the vegetation.
“In the next steps, sociologists and economists on the project will quantify how the innovation affects quality of life and whether it is biased based on wealth, gender and/or age,” Rohr said.
The team will also investigate how biodigesters might be implemented to turn the aquatic vegetation into fertilizer and gas that can be used for cooking or to fuel generators for electricity production. Rohr said they hope to leverage investments by the Swiss government, which has committed to installing 60,000 biodigesters in Senegal for carbon credits.
The ongoing research could not be accomplished without all of the partners who contributed, especially the Senegalese citizens, Rohr said.
Christopher Haggerty, a postdoctoral student at Notre Dame during the study, contributed to this research. A complete list of co-authors can be found on the paper at Nature.
The research was funded by the National Institutes of Health, the National Science Foundation, the Indiana Clinical and Translational Sciences Institute and a Stanford seed grant.

Cancer therapies that target specific genetic abnormalities in tumors have revolutionized treatment possibilities over the past two decades. While quality of life and survival are improved with targeted therapies, relapse is common due to the evolution of new tumor cells that are resistant to the targeted therapy. A new study by investigators from the Mass General Cancer Center, a member of the Mass General Brigham healthcare system, reveals how lung tumors may develop drug resistance over time, pointing to a protein, called APOBEC3A, that could be a promising target. Results, published in Nature, may help researchers develop new solutions for tumor resistance to targeted cancer therapies.
“Traditionally, we treat patients with a drug until the tumor progresses and then we look at what happened in the tumor and try to decide on the next therapy based on what we see in the tumor,” said corresponding author Aaron Hata, MD, PhD, of the Mass General Cancer Center. “In that sense, the tumor is always one step ahead and we need to react to it. By understanding the fundamental mechanisms of tumor evolution, we can get ahead of the tumor, understand what’s driving it, and be able to intervene earlier.”
In this study, the authors analyzed non-small-cell lung cancer (NSCLC) tumor cells treated with tyrosine kinase inhibitors (TKIs), a type of targeted therapy. The researchers performed genetic analysis on patient tumors as well as experimentally derived TKI-resistant cells, finding that in both settings, the small population of tumor cells that survived after TKI treatment accumulated mutations of the APOBEC mutation signature. The authors found that the tumor cells surviving TKI treatment overexpress a type of APOBEC protein, APOBEC3A, which appears to cause drug resistance in two main ways. APOBEC3A can directly cause mutations that are known to result in tumor resistance, such as mutations in the ALK gene. In other cases, the cause of drug resistance is less direct, though the researchers hypothesize that APOBEC3A causes extensive DNA damage that helps push tumor cells into a “persister” state that is more resistant to treatment.
The researchers demonstrated that cell lines without the APOBEC3A gene did not become resistant to targeted therapies as fast as those with the gene. This suggests that targeting APOBEC could extend patients’ response to existing targeted therapies; however, no drug exists yet to target APOBEC.
Going forward, the researchers hope to gain further insight into the mechanisms by which APOBEC causes drug resistance, which may shed more light on how to develop a drug to inhibit APOBEC expression or activity. While many NSCLC patients with targeted therapy-resistant tumors have APOBEC mutations, the patients that do not have these mutations would require other solutions. Furthermore, it is not yet clear whether APOBEC drives acquired drug resistance in other cancer types or with use of other targeted therapies.
“Many new cancer therapies that have been developed in the genomic era specifically target ‘driver mutations,’ such that they do not hurt healthy cells and only affect cells with the mutation driving the tumor progression,” said corresponding author Michael Lawrence, PhD, of the Mass General Cancer Center. “Very often, however, a tumor will return, having undergone a change that allows it to survive in the presence of the drug. Our research helps us understand the mechanisms that drive the process of drug resistance, which begin before the tumor becomes resistant.”

An overdosed gene on chromosome 21 causes people with Down’s Syndrome to age faster than the general population.
The molecular processes responsible for natural ageing of cells are poorly understood. Studying conditions in humans where ageing is accelerated due to genetic causes presents opportunities to learn about the mechanisms that control ageing and devise strategies to slow down the ageing process.
Adults who have Down’s Syndrome (DS) show earlier signs of ageing-related conditions: reduction in tissue regenerative capacity, alopecia, dry skin, delayed wound healing, chronic gum disease, osteoporosis, senescence of the brain and immune cells. DS is a genetic, but not inheritable condition, caused by being born with an extra copy of chromosome 21 (trisomy 21). It affects around 7 million people worldwide (around 60,000 in the UK).
DS is the most frequent genetic cause of intellectual disability and early onset Alzheimer’s disease. While increased risk of early Alzheimer’s is clearly caused by an extra copy of the amyloid precursor protein gene (APP) encoded on chromosome 21, the genetic basis for the other conditions is not easily explainable.
New research published in the Lancet Discovery journal eBioMedicine, led by Queen Mary’s Professor Dean Nižetic and Dr Aoife Murray, with collaborating institutions from Croatia, Singapore, France, Italy and four other London universities, has uncovered an overdosed gene on chromosome 21 causes cells of people with DS to age prematurely.
The study has shown that biological age of people who have DS is on average 19.1 years older than the chronologically age-matched people who don’t have DS. The research has also shown that this is not caused by co-morbidities of DS, and that the premature ageing process starts very early in childhood. The gene for a kinase (a type of enzyme that speed chemical reactions in the body) called DYRK1A was identified as the main cause of the premature ageing component of DS, showing that this gene’s overdose disturbs the DNA-damage-repair mechanisms, causing cells to develop more breaks in their DNA and fragility of their cell nuclei.
Dean Nižetic, Professor of Cell and Molecular Biology at Queen Mary, said:
“We have uncovered that trisomic overdose of this gene (DYRK1A) is one of the main contributors to premature biological ageing in DS. Further research is needed to understand how much this contributes to brain development and function, and also in finding ways of precisely inhibiting the overdose of this gene back to physiological levels. This could open exciting new possibilities for early interventions in DS, but a lot more research is needed.”
Carol Boys, Chief Executive of the Down’s Syndrome Association, commented:
“We have known for a long time that people who have Down’s syndrome experience an ageing process which appears faster than in the general population.
To have a landmark research study like this, published by highly respected researchers, working together on an international basis is a pivotal development. Most importantly, the study hints at the prospect of effective treatments which may intervene in the accelerated cellular ageing process. This aspect of the research will be of huge interest to people who have Down’s syndrome and their families.”
The research has also shown that genetic or chemical reduction of the action of this gene has the potential to correct the cellular ageing defects. This opens possibilities for early therapeutic interventions for people with DS, to diminish the premature biological ageing effects on their development and well-being. These findings also shed more light onto the natural mechanisms of ageing and genes whose actions could be tackled to delay the natural ageing process and reduce the risk of common ageing-related diseases.

When bacteria are attacked by a virus, they can defend themselves with a mechanism that fends off the genetic material introduced by the intruder. The key is CRISPR-Cas protein complexes. It is only in the last decade that their function for adaptive immunity in microorganisms has been discovered and elucidated. With the help of an embedded RNA, the CRISPR complexes recognise a short sequence in the attacker’s DNA. The mechanism of sequence recognition by RNA has since been used to selectively switch off and modify genes in any organism. This discovery revolutionised genetic engineering and was already honoured in 2020 with the Nobel Prize in Chemistry awarded to Emmanuelle Charpentier and Jennifer A. Doudna.
Occasionally, however, CRISPR complexes also react to gene segments that differ slightly from the sequence specified by the RNA. This leads to undesirable side effects in medical applications. “The causes of this are not yet well understood, as the process could not be observed directly until now,” says Dominik Kauert, who worked on the project as a PhD student.
Nanoscale processes tracked in detail
To better understand the recognition process, the team led by Professor Ralf Seidel and Dominik Kauert took advantage of the fact that the DNA double helix of the target sequence is unwound during recognition to enable base pairing with the RNA. “The central question of the project was therefore whether the unwinding of a piece of DNA that is only 10 nanometres (nm) long could be tracked in real time at all,” says Kauert.
To observe the unwinding process in detail, the scientists had to make it visible to the microscope. To achieve this goal, the team drew on the achievements of DNA nanotechnology, which can be used to create any three-dimensional DNA nanostructure. Using this so-called DNA origami technique, the researchers constructed a 75 nm long DNA rotor arm with a gold nanoparticle attached to its end. In the experiment, the unwinding of the 2 nm thin and 10 nm long DNA sequence was transferred to the rotation of the gold nanoparticle along a circle with a diameter of 160 nm — this movement can be magnified and tracked using a special microscope setup.
With this new method, the researchers were able to observe the sequence recognition by the CRISPR Cascade complex almost base pair by base pair. Surprisingly, base pairing with the RNA is not energetically advantageous, meaning that the complex is only unstably bound during sequence recognition. Only when the entire sequence is recognised does stable binding occur and the DNA is subsequently destroyed. If it is the “wrong” target sequence, the process is aborted.
Findings will help in selecting suitable RNA sequences
The fact that the recognition process sometimes produces incorrect results is due to its stochastic nature, i.e. to random molecular movements, as the researchers have now been able to demonstrate. “Sequence recognition is driven by thermal fluctuations in base pairing,” says Kauert. With the data obtained, it was possible to create a thermodynamic model of sequence recognition that describes the recognition of deviating sequence segments. In the future, this should allow better selection of RNA sequences that recognise only the desired target sequence, thus optimising the precision of genetic manipulation.
As the designed nanorotors are universal in their suitability for measuring twists and torques in single molecules, they can also be used for other CRISPR-Cas complexes or biomolecules.
The work was funded by the European Research Council and the German Research Foundation and carried out in collaboration with the research group of Professor Virginijus Siksnys from Vilnius University in Lithuania, who isolated and provided the CRISPR complexes used.

In a major Swedish study, researchers have discovered a link between the levels of certain bacteria living in the gut and coronary atherosclerotic plaques. Such atherosclerotic plaques, which are formed by the build-up of fatty and cholesterol deposits, constitute a major cause of heart attacks. The study was led by researchers at Uppsala and Lund University and the findings have now been published in the scientific journal Circulation.
The new study was based on analyses of gut bacteria and cardiac imaging among 8,973 participants aged 50 to 65 from Uppsala and Malmö without previously known heart disease. They were all participants in the Swedish CArdioPulmonary bioImage Study (SCAPIS).
“We found that oral bacteria, especially species from the Streptococcus genus, are associated with increased occurrence of atherosclerotic plaques in the small arteries of the heart when present in the gut flora. Species from the Streptococcus genus are common causes of pneumonia and infections of the throat, skin and heart valves. We now need to understand whether these bacteria are contributing to atherosclerosis development,” says Tove Fall, Professor in Molecular Epidemiology at the Department of Medical Sciences and the SciLifeLab, Uppsala University, who coordinated the study together with researchers from Lund University.
Advancements in technology have enabled large-scale deep characterisation of bacterial communities in biological samples by sequencing the DNA content and comparing it to known bacteria sequences. Additionally, improvements in imaging techniques have enabled the detection and measurement of early changes in the small vessels of the heart. The SCAPIS study represents one of the largest collections in the world of both these kinds of data. In this study, scientists investigated the links between the gut microbiota and the build-up of fatty deposits in the arteries of the heart.
“The large number of samples with high-quality data from cardiac imaging and gut flora allowed us to identify novel associations. Among our most significant findings, Streptococcus anginosus and S. oralis subsp. oralis were the two strongest ones,” says Sergi Sayols-Baixeras, lead author from Uppsala University.
The research team also found that some of the species linked to the build-up of fatty deposits in heart arteries were linked to the levels of the same species in the mouth. This was measured using faecal and saliva samples collected from the Malmö Offspring Study and Malmö Offspring Dental Study. Furthermore, these bacteria were associated with inflammation markers in the blood, even after accounting for differences in diet and medication between the participants who carried the bacteria and those who did not.
“We have just started to understand how the human host and the bacterial community in the different compartments of the body affect each other. Our study shows worse cardiovascular health in carriers of streptococci in their gut. We now need to investigate if these bacteria are important players in atherosclerosis development,” notes Marju Orho-Melander, Professor in Genetic Epidemiology at Lund University and one of the senior authors of the study.