Publisher Health

Researchers at Karolinska Institutet in Sweden have developed a novel strategy for identifying potent miniature antibodies, so-called nanobodies, against emerging SARS-CoV-2 variants. The approach led to the discovery of multiple nanobodies that in cell cultures and mice effectively blocked infection with different SARS-CoV-2 variants. The findings, which are described in the journals Nature Communications and Science Advances, could pave the way for new treatments against COVID-19.
“With the help of advanced laboratory techniques, we were able to identify a panel of nanobodies that very effectively neutralized several variants of SARS-CoV-2,” says Gerald McInerney, professor at the Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, and joint senior author of both studies.
Despite the roll-out of vaccines and antivirals, the need for effective therapeutics against severe COVID-19 infection remains high. Nanobodies — which are fragments of antibodies that occur naturally in camelids and can be adapted for humans — are promising therapeutic candidates as they offer several advantages over conventional antibodies. For example, they have favourable biochemical properties and are easy to produce cost-effectively at scale.
In the now published studies, the labs of Gerald McInerney and Ben Murrell, also at MTC, identify several potent nanobodies derived from an alpaca immunised with SARS-CoV-2 antigens.
The first report in Nature Communications describes a single nanobody, Fu2 (named after the alpaca Funny), that significantly reduced the viral load of SARS-CoV-2 in cell cultures and mice. Using electron cryo-microscopy, the researchers found that Fu2 naturally binds to two separate sites on the viral spike, thus inhibiting the virus’ ability to enter the host cell. This part of the study was conducted in collaboration with Hrishikesh Das and Martin Hällberg at the Department of Cell and Molecular Biology at Karolinska Institutet.
The researchers next delved deeper into the alpaca’s nanobody repertoire by combining a range of advanced laboratory techniques and computational methods, resulting in a library of nanobodies described in detail.
The results, presented in Science Advances, revealed additional nanobodies that in cell cultures and mice effectively cross-neutralized both the founder and beta variant of SARS-CoV-2 and even neutralized the more distantly related SARS-CoV-1.
“These nanobodies represent promising therapeutic candidates against several SARS-CoV-2 variants,” says first author Leo Hanke, a postdoctoral researcher who established the nanobody technology in the McInerney group.
The researchers are currently applying the same techniques to identify which nanobodies from this set are best able to neutralize Omicron, the now dominating SARS-CoV-2 variant.
“Once established, these libraries can be expanded and mined for nanobodies that neutralize new emerging variants,” says Assistant Professor Ben Murrell, also joint senior author of both studies.
Funding was provided by David and Astrid Hagelén Foundation, the Clas Groschinskys Minnesfond and a Jonas Söderquist’s scholarship, European Union’s Horizon 2020 research and innovation program, Swedish Research Council, and Knut and Alice Wallenberg Foundation.
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A team of scientists has created a powerful new method for generating protein drugs. Using computers, they designed molecules that can target important proteins in the body, such as the insulin receptor, as well as vulnerable proteins on the surface of viruses. This solves a long-standing challenge in drug development and may lead to new treatments for cancer, diabetes, infection, inflammation, and beyond.
The research, appearing March 24 in the journal Nature, was led by scientists in the laboratory of David Baker, professor of biochemistry at the University of Washington School of Medicine and a recipient of the 2021 Breakthrough Prize in Life Sciences.
“The ability to generate new proteins that bind tightly and specifically to any molecular target that you want is a paradigm shift in drug development and molecular biology more broadly,” said Baker.
Antibodies are today’s most common protein-based drugs. They typically function by binding to a specific molecular target, which then becomes either activated or deactivated. Antibodies can treat a wide range of health disorders, including COVID-19 and cancer, but generating new ones is challenging. Antibodies can also be costly to manufacture.
A team led by two postdoctoral scholars in the Baker lab, Longxing Cao and Brian Coventry, combined recent advances in the field of computational protein design to arrive at a strategy for creating new proteins that bind molecular targets in a manner similar to antibodies. They developed software that can scan a target molecule, identify potential binding sites, generate proteins targeting those sites, and then screen from millions of candidate binding proteins to identify those most likely to function.
The team used the new software to generate high-affinity binding proteins against 12 distinct molecular targets. These targets include important cellular receptors such as TrkA, EGFR, Tie2, and the insulin receptor, as well proteins on the surface of the influenza virus and SARS-CoV-2 (the virus that causes COVID-19).
“When it comes to creating new drugs, there are easy targets and there are hard targets,” said Cao, who is now an assistant professor at Westlake University. “In this paper, we show that even very hard targets are amenable to this approach. We were able to make binding proteins to some targets that had no known binding partners or antibodies,”
In total, the team produced over half a million candidate binding proteins for the 12 selected molecular targets. Data collected on this large pool of candidate binding proteins was used to improve the overall method.
“We look forward to seeing how these molecules might be used in a clinical context, and more importantly how this new method of designing protein drugs might lead to even more promising compounds in the future,” said Coventry.
The research team included scientists from the University of Washington School of Medicine, Yale University School of Medicine, Stanford University School of Medicine, Ghent University, The Scripps Research Institute, and the National Cancer Institute, among other institutions.
This work was supported in part by The Audacious Project at the Institute for Protein Design, Open Philanthropy Project, National Institutes of Health (HHSN272201700059C, R01AI140245, R01AI150855, R01AG063845), Defense Advanced Research Project Agency (HR0011835403 contract FA8750-17-C-0219), Defense Threat Reduction Agency (HDTRA1-16-C-0029), Schmidt Futures, Gates Ventures, Donald and Jo Anne Petersen Endowment, and an Azure computing gift for COVID-19 research provided by Microsoft.

University of Notre Dame researchers have discovered another way tumor cells transfer genetic material to other cells in their microenvironment, causing cancer to spread.
In their latest study, published in Cell Reports, Crislyn D’Souza-Schorey, the Morris Pollard Professor in the Department of Biological Sciences, and collaborators discovered that DNA “cargo” is transported in small informational sacs called extracellular microvesicles. Their study is a continuation of work her lab has undertaken to further understand the sharing of information between cells.
“We’ve shown that DNA present in these microvesicles is related to metastasis, so now we have a great platform to assess for genetic aberrations,” said D’Souza-Schorey, who is also affiliated with the Berthiaume Institute for Precision Health, the Boler-Parseghian Center for Rare and Neglected Diseases and the Harper Cancer Research Institute.
Cancer cells, unlike normal cells, are often filled with cytosolic DNA, which is DNA found in the jelly-like fluid outside of the cell’s nucleus. This DNA can be derived from multiple sources, but recent evidence suggests that chromosomal instability is a primary source of cytosolic DNA in tumor cells.
The research team used a cell model from a male cancer patient to show how Y-chromosomal DNA — present in the cytosol due to chromosomal instability — is carried by extracellular vesicles and transferred to a female mammary epithelial cell line.
“These female cells do not have Y-chromosomal DNA present without exposure to the male microvesicles,” said James Clancy, research assistant professor of biological sciences, who is the first author on the paper. “This is an accessible way to show people that the DNA was transferred, making it easier to prove this form of communication.”
The researchers demonstrated that cytosolic DNA is moved to microvesicles alongside an enzyme, cGAS, which was discovered in part because of its role during the immune response to bacterial and viral infections. Scientists have increasingly recognized that cGAS may play a part in tumor progression, and this new study delineated a way the DNA is modified to aid that progression.
Work published by D’Souza-Schorey’s lab in 2019 in Nature Cell Biology described how microRNA within tumor cells is moved to microvesicles just beginning to form at the cell periphery. Once shed, these vesicles are taken up by non-tumor cells in the microenvironment. Microvesicles can also be found circulating through the body in fluids like blood and urine, and can be used as biomarkers that point to the presence of cancer.
While microRNA can affect protein expression more quickly than DNA, the researchers were interested in the DNA content as it is the actual part of a person’s genome, including any tumor-associated mutations, Clancy said. It was also more difficult to prove that DNA has moved from one cell to another.
The lab’s continued foundational research in this area may lead to early detection of different types of tumors.
In addition to D’Souza-Schorey and Clancy, others who worked on the study include Colin Sheehan, class of ’19, and Alex C. Boomgarden, a fourth-year doctoral student at Notre Dame and recipient of a Berthiaume Institute for Precision Health predoctoral fellowship. Sheehan is now pursuing his doctoral degree at the University of Chicago. The study was supported in part by the National Cancer Institute and the Boler Family Foundation.
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Materials provided by University of Notre Dame. Original written by Deanna Csomo Ferrell. Note: Content may be edited for style and length.

Researchers from the Babraham Institute’s Epigenetics research programme have been able to learn more about naïve stem cell reprogramming following a genome wide functional screen. Their research, published today in Science Advances, describes the critical regulators of reprogramming and offers opportunities for a more efficient, faster way to generate human naïve pluripotent stem cells.
Human pluripotent stem cells (PSCs) are a useful tool for researchers investigating how cells specialise to make every tissue of our body. They come in two different states, primed and naïve. Both types of PSC can self-renew and differentiate into new cell types but they have distinct functions and molecular characteristics.
Group leader Peter Rugg-Gunn explained the importance of these cells: “Human PSCs in the naïve state replicate the key molecular and cellular characteristics of cells in a pre-implantation stage embryo. Importantly, when naïve PSCs are encouraged to self-organise in particular conditions, they form structures that resemble an early blastocyst stage of development. By growing these cells in the lab, we can learn about the key events that happen during human development, and they have potential uses in personalised medicine. But we need to create high-quality, stable stem cell populations to be able to conduct our experiments.”
Pluripotent stem cells are formed either from embryos or using Nobel Prize-winning methods to remove cell identity from specialised cells. The majority of reprogramming experiments generate primed PSCs, which are more developmentally advanced than naïve PSCs. Naïve PSCs can be collected directly from human pre-implantation embryos, or more commonly researchers expose primed PSCs to conditions that induces them to become naïve PSCs. Existing methods for reprogramming were inefficient and slow, preventing researchers’ from quickly producing the numbers of high-quality stem cells they needed.
Adam Bendall, PhD student and a lead researcher on the study, said: “Very little was known about what genetic and epigenetic factors are required for naïve cell reprogramming, and this knowledge gap limited the design of reprogramming conditions.”
The low efficiency of naïve reprogramming suggests the presence of barriers that limit cells in reaching the naïve state. Adam and his colleagues honed in on these barriers by performing a large-scale genetic screen to identify genes that hinder and help reprogramming. They were able to identify a large number of genes that have a crucial role in naïve PSC programming that had not been previously linked to the process.
The team focused on one epigenetic complex in particular, the PRC1.3 complex, that regulates gene expression without altering the underlying DNA sequence, and which they found to be essential for the formation of naïve PSCs. Without this complex, the cells undergoing reprogramming become a completely different type of cell rather than naïve PSCs. This suggests that the activity of PRC1.3 could encourage more cells to reprogram properly, in effect lowering the barrier.
After identifying factors that promote reprogramming, the researchers also looked at factors that impede reprogramming, exemplified in their study by an epigenetic protein called HDAC2. Dr Amanda Collier, first author on the paper, explained: “Excitingly, when we inhibited one of these factors using selective chemicals, then naïve PSC reprogramming occurred more efficiently and rapidly. We’re able to look at it from both sides; we can remove the barriers and introduce the factors that push cells towards state change.”
Not only does this research improve scientists’ ability to produce human naïve PSCs, it provides details on the molecular events that occur during the cell state transition itself, some of which are conserved in developmental regulation in human embryos.
The Rugg-Gunn lab are putting together the pieces of a bigger puzzle — the best understanding of the formation and control of naïve stem cells. Their previous research has identified molecular factors that help to maintain cells in a naïve stage. Group leader, Peter Rugg-Gunn said: “By building up our tools for manipulating pluripotent stem cells, we can spend more time asking important questions about the pre-implantation embryo. In the longer term, further improvements in working with naïve PSCs might open up the possibility for using these cells in personalised disease models or cell therapies, although this will require more research on how to differentiate naïve PSCs into specialised cell types.”
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The A2A receptor regulates how vigorously the innate immune system attacks diseased cells. Researchers at the University of Bonn have now been able to show for the first time how an important inhibitor binds to the receptor. In the future, the results will facilitate the targeted search for molecules that give the innate immune system more punch. These could for instance be used in the fight against cancer, but also against brain diseases such as Alzheimer’s or Parkinson’s disease. The final version of the study has been published in the journal Angewandte Chemie International Edition.
Anyone who enjoys reading thrillers knows: Before thieves break into a mansion, they like to toss a juicy chop over the fence, in which they have hidden a few sleeping pills. When the watchdogs get down to their second dinner, they succumb to deep slumber shortly thereafter. The jewels of the lady of the house change hands much more unperturbed after that.
Tumor cells often proceed in a very similar way: They cast out sleeping pills that paralyze the immune system. More specifically, they surround themselves with a cloud of adenosine, an important endogenous messenger. In this way, they disable the body’s own “killer cells,” which would otherwise cause the cancer cells to die.
This is because the adenosine molecules bind to tiny antennae on the surface of the immune cells, the A2A receptors (the abbreviation stands for “type 2A adenosine receptors”). This knocks out the defensive troops, so to speak. Researchers around the globe are therefore looking for molecules that can block the A2A receptor and prevent the paralyzing effect of adenosine.
Bombardment with X-rays
“Our study should make this search a lot easier,” explains Prof. Dr. Christa Müller of the Pharmaceutical Institute of the University of Bonn. “We have added novel variants of a known inhibitor, a substance called preladenant, to the A2A receptor. Then we created crystals from the receptor-inhibitor complexes — it’s the first time in the world that this has been achieved with preladenant-like substances.”
Crystallization made it possible to elucidate the structure of the complex. “To do this, we bombard the compound with X-rays,” explains Tobias Claff, who performed the main part of the experiments. “The crystal diffracts the rays. The way it does this then allows us to deduce the spatial structure of the complex — right down to the arrangement of individual atoms and their interactions.”

A study led by UC Davis Health has found that half of all women will experience at least one false positive mammogram over a decade of annual breast cancer screening with digital breast tomosynthesis (3D mammography). The risk of false positive results after 10 years of screening is considerably lower in women screened every other year. A false positive is when a mammogram is flagged as abnormal, but there is no cancer in the breast.
The study was published today in JAMA Network Open.
It also showed that repeated breast cancer screening with 3D mammography only modestly decreases the chance of having a false positive result compared with the standard digital 2D mammography. Other factors more strongly linked to a lower false positive risk included screening every other year and having non-dense breasts. Older women were also less likely to have a false positive result.
“The screening technology did not have the largest impact on reducing false positives,” said Michael Bissell, epidemiologist in the UC Davis Department of Public Health Sciences and co-first author of the study. “Findings from our study highlight the importance of patient-provider discussions around personalized health. It is important to consider a patient’s preferences and risk factors when deciding on screening interval and modality.”
False positive mammograms are common
Breast cancer is the second leading cause of cancer-related death for women in the U.S. Early detection using screening mammography is a key strategy to lower the risk of advanced breast cancer and death from this disease.

Observational research has suggested that light alcohol consumption may provide heart-related health benefits, but in a large study published in JAMA Network Open, alcohol intake at all levels was linked with higher risks of cardiovascular disease. The findings, which are published by a team led by researchers at Massachusetts General Hospital (MGH) and the Broad Institute of MIT and Harvard, suggest that the supposed benefits of alcohol consumption may actually be attributed to other lifestyle factors that are common among light to moderate drinkers.
The study included 371,463 adults — with an average age of 57 years and an average alcohol consumption of 9.2 drinks per week — who were participants in the UK Biobank, a large-scale biomedical database and research resource containing in-depth genetic and health information. Consistent with earlier studies, investigators found that light to moderate drinkers had the lowest heart disease risk, followed by people who abstained from drinking. People who drank heavily had the highest risk. However, the team also found that light to moderate drinkers tended to have healthier lifestyles than abstainers — such as more physical activity and vegetable intake, and less smoking. Taking just a few lifestyle factors into account significantly lowered any benefit associated with alcohol consumption.
The study also applied the latest techniques in a method called Mendelian randomization, which uses genetic variants to determine whether an observed link between an exposure and an outcome is consistent with a causal effect — in this case, whether light alcohol consumption causes a person to be protected against cardiovascular disease. “Newer and more advanced techniques in ‘non-linear Mendelian randomization’ now permit the use of human genetic data to evaluate the direction and magnitude of disease risk associated with different levels of an exposure,” says senior author Krishna G. Aragam, MD, MS, a cardiologist at MGH and an associate scientist at the Broad Institute. “We therefore leveraged these new techniques and expansive genetic and phenotypic data from biobank populations to better understand the association between habitual alcohol intake and cardiovascular disease.”
When the scientists conducted such genetic analyses of samples taken from participants, they found that individuals with genetic variants that predicted higher alcohol consumption were indeed more likely to consume greater amounts of alcohol, and more likely to have hypertension and coronary artery disease. The analyses also revealed substantial differences in cardiovascular risk across the spectrum of alcohol consumption among both men and women, with minimal increases in risk when going from zero to seven drinks per week, much higher risk increases when progressing from seven to 14 drinks per week, and especially high risk when consuming 21 or more drinks per week. Notably, the findings suggest a rise in cardiovascular risk even at levels deemed “low risk” by national guidelines from the U.S. Department of Agriculture (i.e. below two drinks per day for men and one drink per day for women).
The discovery that the relationship between alcohol intake and cardiovascular risk is not a linear one but rather an exponential one was supported by an additional analysis of data on 30,716 participants in the Mass General Brigham Biobank. Therefore, while cutting back on consumption can benefit even people who drink one alcoholic beverage per day, the health gains of cutting back may be more substantial — and, perhaps, more clinically meaningful — in those who consume more.
“The findings affirm that alcohol intake should not be recommended to improve cardiovascular health; rather, that reducing alcohol intake will likely reduce cardiovascular risk in all individuals, albeit to different extents based on one’s current level of consumption,” says Aragam.
The study’s lead author was Kiran J. Biddinger, and additional authors included Connor A. Emdin, MD, DPhil, Mary E. Haas, PhD, Minxian Wang, PhD, George Hindy, MD, Patrick T. Ellinor, MD, PhD, Sekar Kathiresan, MD, and Amit V. Khera, MD, MSc.
Funding was provided by the National Institutes of Health and the American Heart Association.
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A team of researchers from the National University of Singapore (NUS) has developed a novel super-hygroscopic material that enhances sweat evaporation within a personal protective suit, to create a cooling effect for better thermal comfort for users such as healthcare workers and other frontline officers. This invention was validated through laboratory tests conducted in collaboration with researchers from HTX (Home Team Science & Technology Agency) in Singapore.
The new desiccant film, which is biocompatible and non-toxic, has fast absorption rate, high absorption capacity and excellent mechanical properties. This means that the material is very robust and durable for practical applications such as for protective suits worn by healthcare workers. It is also affordable, light-weight, easy to fabricate and reusable.
“Under room temperature of about 35deg C, a healthcare worker who dons a protective suit for one hour typically experiences a heat index of about 64 deg C. This causes discomfort and prolong thermal strain can result in heat stroke and even death. Our novel composite moisture-trapping film achieves a cooling effect within the protective suit via evaporative cooling — by increasing sweat evaporation from the skin,” explained research team leader Assistant Professor Tan Swee Ching, who is from the Department of Materials Science and Engineering under the NUS College of Design and Engineering.
Attaching a piece of novel composite film in a protective suit — for example at the back of the suit — could bring down the heat index by about 40%, remarkably lowering the likelihood of heat stroke.
This invention was published in the scientific journal Small on 20 February 2022.
This research breakthrough demonstrates the positive outcome of leveraging the complementary strengths of NUS and HTX to create tangible benefits for the Home Team and the wider community. By combining the NUS team’s scientific knowledge of advanced hydrogel materials and HTX’s deep understanding of the Home Team’s needs and engineering capabilities, the joint research team was able to customise and optimise the novel moisture-trapping material for practical applications to enhance the performance and productivity of frontline officers.

Adding to a growing body of evidence that, for many, problems related to COVID-19 linger longer than the initial infection, researchers at Washington University School of Medicine in St. Louis have found that some people infected during the pandemic’s early months experienced peripheral neuropathy — pain, tingling and numbness in the hands and feet — during and following their bouts with the virus.
In a study of more than 1,500 people who were tested for SARS-CoV-2 during the first year of the pandemic, the researchers found that those who tested positive for the virus were about three times more likely to report pain, numbness or tingling in their hands and feet as those with negative tests.
The findings are reported online March 24 in the journal Pain.
“Several viral infections — such as HIV and shingles — are associated with peripheral neuropathy because viruses can damage nerves,” said senior investigator Simon Haroutounian, PhD, chief of clinical research at the Washington University Pain Center. “We found that nearly 30% of patients who tested positive for COVID-19 also reported neuropathy problems at the time of their diagnosis, and that for 6% to 7% of them, the symptoms persisted for at least two weeks, and up to three months, suggesting this virus may have lingering effects on peripheral nerves.”
Haroutounian, who also is an associate professor of anesthesiology and director of the department’s Division of Clinical and Translational Research, said some patients who traced the start of their neuropathy symptoms to a COVID-19 infection have sought treatment at the Washington University Pain Center. Most of those in the study, however, reported problems that were rated as mild to moderate and may not have sought help from a pain specialist.
“It is important to understand whether a viral infection is associated with an increased risk of neuropathy,” he said. “In the case of HIV, we didn’t realize it was causing neuropathy for several years after the AIDS epidemic began. Consequently, many people went undiagnosed with neuropathy and untreated for the pain associated with the problem.”
He said the same may be true now for patients with neuropathy following COVID-19. There is no established diagnosis of neuropathy related to COVID-19, but Haroutounian explained that, regardless of the cause, current treatments for neuropathy are somewhat similar. Pain specialists use the same types of medications to treat peripheral neuropathy, whether it’s caused by diabetes or HIV or the cause is unclear.

It is widely recognised that a longer ring finger is a marker of higher levels of testosterone prenatally, whereas a longer index finger is a marker of higher levels of oestrogen. Generally, men have longer ring fingers, whereas women have longer index fingers.
New research involving Swansea University is examining the link between levels of sex hormones in the womb and in puberty and Covid hospitalizations.
Most people who contract the virus only experience mild symptoms. But when it comes to patients who need hospital care, the rates vary depending on age (with elderly people the most affected) and gender (with males experiencing a higher severity than females).
This has led scientists to examine the link between testosterone and Covid-19 severity more closely. One hypothesis implicates high testosterone in severe cases but another links low levels of testosterone in elderly men with a poor prognosis.
Now Professor John Manning, of the Applied Sports Technology, Exercise and Medicine (A-STEM) research team, has been working with colleagues from the Medical University of Lodz in Poland and Sweden’s Karolinska University Hospital to look more closely at digit ratios (ratios of the 2nd, 3rd, 4th and 5th digits) as predictors of severity of Covid-19 symptoms.
The researchers observed that patients with “feminized” short little fingers relative to their other digits tend to experience severe Covid-19 symptoms leading to hospitalization, and more importantly patients with large right hand — left hand differences in ratios 2D:4D and 3D:5D — have substantially elevated probabilities of hospitalization.